2-(2-Hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors

ABSTRACT

The present invention relates to novel inhibitors of Factors VIIa, IXa, Xa, XIa, in particular Factor VIIa, pharmaceutical compositions comprising these inhibitors, and methods for using these inhibitors for treating or preventing thromboembolic disorders, cancer or rheumatoid arthritis. Processes for preparing these inhibitors are also disclosed.

BACKGROUND OF THE INVENTION

1. Field of invention

The present invention relates to novel inhibitors of Factors VIIa, IXa,Xa, XIa, in particular Factor VIIa, pharmaceutical compositionscomprising these inhibitors, and methods for using these inhibitors fortreating or preventing thromboembolic disorders. Processes for preparingthese inhibitors are also disclosed.

2. State of the Art

Thrombosis results from a complex sequence of biochemical events, knownas the coagulation cascade. A triggering event in coagulation is thebinding of the serine protease Factor VIIa (FVIIa) found in thecirculation, to tissue factor (TF), a receptor which is found on thesurface of blood vessels after damage or inflammation. Once bound to TF,Factor VIIa catalyzes the formation of the serine protease Factor Xa,which subsequently forms the final protease in the cascade, thrombin.

The clinical manifestations of thrombosis range from acute myocardialinfarction (AMI or heart attack) and unstable angina (UA) which occur inthe key blood vessels of the heart (coronary vasculature) to deep veinthrombosis (DVT) which is the formation of blood clots in lowerextremities which often follows orthopedic surgery on the hip and knee,as well as general abdominal surgery and paralysis. Formation of DVT isa risk factor for the development of pulnonary embolism (PE) in whichpart of a blood clot formed in the lower extremities, breaks off andtravels to the lung where it blocks the flow of blood. The unpredictabledevelopment of PE often leads to a fatal outcome. Thrombosis can also begeneralized systemically, with microclot formation occurring throughoutthe vascular system. This condition, known as disseminated intravascularcoagulation ([)IC), can be a consequence of certain viral diseases suchas Ebola, certain cancers, sepsis and rheumatoid arthritis. Severe DICcan lead to a dramatic reduction in the coagulation factors due to theexcessive activation of the clotting response which may result inmultiple organ failure, hemorrhage and death.

The formation or embolization of blood clots in the blood vessels of thebrain is the key event resulting in ischemic stroke. Triggering factorsthat lead to stroke are atrial fibrillation or abnormal rhythm of theatria of the heart and atherosclerosis followed by thrombosis in themain artery leading from the heart to the brain (carotid artery). Over600,000 individuals suffer strokes each year in the U.S. Two-thirds ofthese stroke victims suffer some disability, and one-third sufferpermanent and severe disability. Accordingly, there is a need forantithrombotic agents for the treatment of a variety of thromboticconditions. The present invention fulfills this and related needs.

SUMMARY OF THE INVENTION

In one aspect this invention is directed to a compound of Formula I:

wherein:

X¹, X², X³, and X⁴ are independently —N— or —CR⁵— wherein R⁵ ishydrogen, alkyl, or halo with the proviso that not more than three ofX¹, X², X³ and X⁴ are —N—;

R¹ is hydrogen, alkyl, halo, carboxy or aminocarbonyl;

R² is hydrogen, alkyl, or halo;

R³ is hydrogen, halo, alkyl, alkoxy, haloalkyl, haloalkoxy,haloalkylthio, haloalkylsulfonyl, cyanoalkyl, tetrazol-5-yl,-(alkylene)-tetrazol-5-yl, hydroxyalkylcarbonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, —NHSO₂R (where R is alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl or heterocycloalkylalkyl), —SO₂NHCOR⁶ (where R⁶ isalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, orheterocycloalkylalkyl), —SO₃H, -(alkylene)—SO₃H, —CONR⁷R⁸ (where R⁷ ishydrogen, alkyl, hydroxyalkyl, alkoxyalkyl and R⁸ is hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or hetereocycloalkylalkyl, or R⁷ and R⁸ together with thenitrogen atom to which they are attached form heterocycloalkylamino),-(alkylene)-CONR⁹R¹⁰ (where R⁹ is hydrogen, alkyl, hydroxyalkyl,alkoxyalkyl and R¹⁰ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocycloalkylalkyl, or R⁹ and R¹⁰ together with the nitrogen atom towhich they are attached form heterocycloalkylamino), —CONHSO₂R¹¹ (whereR¹¹ is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclalkyl,or heterocycloalkylalkyl), -(alkylene)-CONHSO₂R¹¹ (where R¹¹ is alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, orheterocycloalkylalkyl), aminoalkyloxy, carboxyalkyloxy,aminocarbonylalkyloxy, hydroxyalkyloxy, —O—(CH₂CH₂—O)_(n)—OR^(b) (wheren is an integer from 1 to 6 and R^(b) is hydrogen or alkyl),—NHCO-(alkylene)-R^(a) (where R^(a) is hydroxy, alkoxy, or —NR⁷R⁸ whereR⁷ and R⁸ are as defined above), —OPO₃H₂, or -(alkylene)-OPO₃H₂;

R^(x) is hydrogen, alkyl, alkylthio, halo, hydroxy, hydroxyalkyl,alkoxy, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, ornitro;

R^(y) is hydrogen, alkyl, or halo;

R^(z) is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio, halo,hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl,alkoxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy, carboxyalkyloxy,aminocarbonylalkyloxy, haloalkoxy, carboxy, carboxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl,alkylsulfonylalkyl, arylsulfonyl, heteroarylsulfonyl, carbamimidoyl,hydroxycarbamnimidoyl, alkoxycarbaminidoyl, alkylsulfonylamino,alkylsulfonylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl,heterocycloalkylalkylaminocarbonyl, hydroxyalkoxyalkylaminocarbonyl,heterocycloalkylcarbonyl, heterocycloalkylcarbonylalkyl,heterocycloalkyl, heterocycloalkylalkyl, oxoheterocycloalkyl,oxoheterocycloalkylalkyl, heteroaryl, heteroaralkyl, ureido,alkylureido, dialkylureido, ureidoalkyl, alkylureidoalkyl,dialkylureidoalkyl, thioureido, thioureidoalkyl, —COR¹² (where R¹² isalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl),-(alkylene)-COR¹² (where R¹² is alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, or aminoalkyl), —CONR¹⁴R¹⁵ (where R¹⁴ is hydrogen or alkyland R¹⁵ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl), -(alkylene)-CONR¹⁶R¹⁷ (where R¹⁶ ishydrogen, alkyl or hydroxyalkyl and R¹⁷ is hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl),—NR¹⁸R¹⁹ (where R¹⁸ is hydrogen or alkyl and R¹⁹ is hydrogen, alkyl,acyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR²⁰R²¹(where R²⁰ is hydrogen, alkyl, or hydroxyalkyl and R²¹ is hydrogen,alkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl), —SO₂NR²²R²³ (where R²² is hydrogen oralkyl and R²³ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl, or R²² and R²³ together with the nitrogen atom to whichthey are attached from heterocycloamino), -(alkylene)-SO₂NR²⁴R²⁵ (whereR²⁴ is hydrogen or alkyl and R²⁵ is hydrogen, alkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl or R²⁴ and R²⁵ together with the nitrogenatom to which they are attached from heterocycloamino), —NR²⁶SO₂NR²⁷R²⁸(where R²⁶ and R²⁷ are independently hydrogen or alkyl, and R²⁸ ishydrogen, alkyl, aryl, aralkyl heteroaryl, or heteroaralkyl or R²⁷ andR²⁸ together with the nitrogen atom to which they are attached fromheterocycloamino), -(alkylene)-NR²⁹SO₂NR³⁰R³¹ (where R²⁹ and R³⁰ areindependently hydrogen or alkyl, and R³¹ is hydrogen, alkyl, aryl,aralkyl, heteroaryl, or heteroaralkyl or R³⁰ and R³¹ together with thenitrogen atom to which they are attached from heterocycloamino),—CONH-(alkylene)-NR³²R³³ where R³² is hydrogen or alkyl and R³³ isalkyl), or aralkyl; and

R¹³ is hydrogen, hydroxy, (C₁₋₁₀)alkoxy, —C(O)R³⁵ where R³⁵ is alkyl,aryl, haloalkyl, or cyanoalkyl, or —C(O)OR³⁶ where R³⁶ is alkyl,hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, acyl, aryl, orhaloalkyl; and

individual isomers, mixture of isomers, or a pharmaceutically acceptablesalt thereof, provided that when R³ is hydrogen, halo, alkyl, alkoxy,haloalkyl, haloalkoxy, —NHSO₂R, tetrazol-5-yl,-(alkylene)-tetrazol-5-yl, —CONR⁷R⁸ (where R⁷ is hydrogen or alkyl, andR⁸ is hydrogen or alkyl), -alkylene)-CONR⁹R¹⁰ (where R⁹ and R¹⁰ togetherwith the nitrogen atom to which they are attached form pyrrolidinyl),aminoalkyloxy, carboxyalkyloxy, or aminocarbonylalkyloxy; and R^(z) ishydrogen, alkyl, haloalkyl, halo, nitro, alkoxy, haloalkyl, carboxy,alkoxycarbonyl, —NR¹⁸R¹⁹ (where R¹⁸ is hydrogen or alkyl and R¹⁹ ishydrogen, alkyl, aryl or aralkyl), pyrrolidinylcarbonyl, —SO₂NR²²R²³(where R²² and R²³ are alkyl), carbamimidoyl, alkylsulfonylamino,alkylthio, ureido, —NHC(S)NH₂ or heterocycloamino, then R^(x) is hydroxyor hydroxyalkyl.

In one aspect this invention is directed to a compound of Formula I:

wherein:

X¹, X², X³, and X⁴ are independently —N— or —CR⁵— wherein R⁵ ishydrogen, alkyl, or halo with the proviso that not more than three ofX¹, X², X³ and X⁴ are —N—;

R¹ is hydrogen, alkyl, halo, carboxy or aminocarbonyl;

R² is hydrogen, alkyl, or halo;

R³ is hydrogen, halo, alkyl, alkoxy, haloalkyl, haloalkoxy,haloalkylthio, haloalkylsulfonyl, cyanoalkyl, tetrazol-5-yl,tetrazol-5-ylalkyl, hydroxyalkylcarbonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, oxalyl, —NHSO₂R (where R isalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl), —SO₂NHCOR⁶(where R⁶ is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, or heterocycloalkylalkyl), —SO₃H, -(alkylene)-SO₃H,—CONR⁷R⁸, —CHCF₃NR⁷R⁸ or —COCONR⁷R⁸ (where R⁷ is hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, carboxyalkyl, sulfoalkyl or phosphonoalkyland R⁸ is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl,aminocarbonylcarboxyalkyl, tnmethylammonioalkyl, aminocarbonylalkyl,-(alkylene)-(OCH₂CH₂)_(n) R^(b) (where n is an integer from 1 to 6 andR^(b) is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino),aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl,hetereocycloalkylaminocarbonylalkyl or3-heterocycloalkyl-2-hydroxypropyl or R⁷ and R⁸ together with thenitrogen atom to which they are attached form heterocycloalkylamino),-(alkylene)-CONR⁹R¹⁰ or -(alkylene)-CHCF₃NR⁹R¹⁰ (where R⁹ is hydrogen,hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl,sulfoalkyl or phosphonoalkyl and R¹⁰ is hydrogen, hydroxy, alkyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl,phosphonoalkyl, aminocarboxyalkyl, aminocarbonylcarboxyalkyl,trimethylammonioalkyl, aminocarbonylalkyl, -(alkylene)-(OCH₂CH₂)_(n)R^(b) (where n is an integer from 1 to 6 and R^(b) is hydrogen, alkyl,hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl,heteroaryl, heteroaralkyl, hetereocycloalkylalkyl,hetereocycloalkylaminocarbonylalkyl or3-heterocycloalkyl-2-hydroxypropyl or R⁹ and R¹⁰ together with thenitrogen atom to which they are attached form heterocycloalkylamino),—CONHSO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclalkyl, or heterocycloalkylalkyl),-(alkylene)-CONHSO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl),aminoalkyloxy, carboxyalkyloxy, aminocarbonylalkyloxy, hydroxyalkyloxy,—(OCH₂CH₂)_(n)—R^(b) (where n is an integer from 1 to 6 and R^(b) ishydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino),—NHCO-(alkylene)-R^(a) (where R^(a) is hydroxy, alkoxy, or —NR⁷R⁸ whereR⁷ and R⁸ are as defined above), —OPO₃H₂, or -(alkylene)-OPO₃H₂;

R^(x) is hydrogen, alkyl, alkylthio, halo, hydroxy, hydroxyalkyl,alkoxy, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, ornitro;

R^(y) is hydrogen, alkyl, or halo;

R^(z) is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio, halo,hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl,alkoxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy, carboxyalkyloxy,aminocarbonylalkyloxy, haloalkoxy, carboxy, carboxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl,alkylsulfonylalkyl, arylsulfonyl, heteroarylsulfonyl, carbamimidoyl,hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino,alkylsulfonylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl,heterocycloalkylalkylaminocarbonyl, hydroxyalkoxyalkylaminocarbonyl,heterocycloalkylcarbonyl, heterocycloalkylcarbonylalkyl,heterocycloalkyl, heterocycloalkylalkyl, oxoheterocycloalkyl,oxoheterocycloalkylalkyl, heteroaryl, heteroaralkyl, ureido,alkylureido, dialkylureido, ureidoalkyl, alkylureidoalkyl,dialkylureidoalkyl, thioureido, thioureidoalkyl, —COR¹² (where R¹² isalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl),-alkylene)-COR¹² (where R¹² is alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, or aminoalkyl), —CONR¹⁴R¹⁵ (where R¹⁴ is hydrogen or alkyland R¹⁵ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl,heteroaryl or heteroaralkyl or R¹⁴ and R¹⁵ together with the nitrogenatom to which they are attached from heterocycloamino),-(alkylene)-CONR¹⁶R¹⁷ (where R¹⁶ is hydrogen, alkyl or hydroxyalkyl andR¹⁷ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl,heteroaryl or heteroaralkyl or R¹⁴ and R¹⁵ together with the nitrogenatom to which they are attached from heterocycloamino), —NR¹⁸R¹⁹ (whereR¹⁸ is hydrogen or alkyl and R¹⁹ is hydrogen, alkyl, acyl, aryl,aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR²⁰R²¹ (where R²⁰is hydrogen, alkyl, or hydroxyalkyl and R²¹ is hydrogen, alkyl, acyl,alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl orheteroaralkyl), —SO₂NR²²R²³ (where R²² is hydrogen or alkyl and R²³ ishydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl or R²² andR²³ together with the nitrogen atom to which they are attached fromheterocycloamino), -(alkylene)-SO₂NR²⁴R²⁵ (where R²⁴ is hydrogen oralkyl and R²⁵ is hydrogen, alkyl, aryl, aralkyl, heteroaryl orheteroaralkyl or R²⁴ and R²⁵ together with the nitrogen atom to whichthey are attached from heterocycloamino), —NR²⁶SO₂NR²⁷R²⁸ (where R²⁶ andR²⁷ are independently hydrogen or alkyl, and R²⁸ is hydrogen, alkyl,aryl, aralkyl, heteroaryl or heteroaralkyl or R²⁷ and R²⁸ together withthe nitrogen atom to which they are attached from heterocycloamino),-(alkylene)-NR²⁹SO₂NR³⁰R³¹ (where R²⁹ and R³⁰ are independently hydrogenor alkyl, and R³¹ is hydrogen, alkyl, aryl, aralkyl, heteroaryl orheteroaralkyl or R³⁰ and R³¹ together with the nitrogen atom to whichthey are attached from heterocycloamino), —CONH-(alkylene)-NR³²R³³ whereR³² is hydrogen or alkyl and R³³ is alkyl), or aralkyl; and

R¹³ is hydrogen, hydroxy, (C₁₋₁₀)alkoxy, —C(O)R³⁵ where R³⁵ is alkyl,aryl, haloalkyl, or cyanoalkyl, or —C(O)OR³⁶ where R³⁶ is alkyl,hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, acyl, aryl, orhaloalkyl; and

individual isomers, mixture of isomers, or a pharmaceutically acceptablesalt thereof, provided that when R³ is hydrogen, halo, alkyl, alkoxy,haloalkyl, haloalkoxy, —NHSO₂R, tetrazol-5-yl, tetrazol-5-ylalkyl,—CONR⁷R⁸ (where R⁷ is hydrogen or alkyl, and R⁸ is hydrogen or alkyl),-(alkylene)-CONR⁹R¹⁰ (where R⁹ and R¹⁰ together with the nitrogen atomto which they are attached form pyrrolidinyl), aminoalkyloxy,carboxyalkyloxy, or aminocarbonylalkyloxy; and R^(z) is hydrogen, alkyl,haloalkyl, halo, nitro, alkoxy, haloalkyl, carboxy, alkoxycarbonyl,—NR¹³R¹⁹ (where R¹⁸ is hydrogen or alkyl and R¹⁹ is hydrogen, alkyl,aryl or aralkyl), pyrrolidinylcarbonyl, —SO₂NR²²R²³ (where R²² and R²³are alkyl), carbamimidoyl, alkylsulfonylamino, alkylthio, ureido,—NHC(S)NH₂ or heterocycloamino, then R^(x) is hydroxy or hydroxyalkyl.

In a second aspect, this invention is directed to a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof. The pharmaceutical compositioncan contain individual stereoisomers or mixtures of stereoisomers of acompound of Formula I.

In a third aspect, this invention is directed to a method of treating adisease in an animal that is mediated by Factors VIIa, IXa, Xa and/orXIa, preferably VIIa, which method comprises administering to saidanimal a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundof Formula I or a pharmaceutically acceptable salt thereof. Thepharmaceutical composition can contain individual stereoisomers ormixture of stereoisomers of a compound of Formula I. Preferably, thedisorder is a thromboembolic disorder or cancer or rheumatoid arthritis,more preferably a thromboembolic disorder.

In a fourth aspect, this invention is directed to a method of treating athromboembolic disorder in an animal which method comprisesadministering to said animal a pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof in combination with another anticoagulant agent(s) independentlyselected from a group consisting of a thrombin inhibitor, factor IXainhibitor, factor Xa inhibitor, Aspirin®, and Plavix®.

In a fifth aspect, this invention is directed to a method for inhibitingthe coagulation of a biological sample (e.g., stored blood products andsamples) comprising the administration of a compound of Formula I or apharmaceutically acceptable salt thereof.

In a sixth aspect, this invention directed to the use of a compound ofFormula I or a pharmaceutically acceptable salt thereof in thepreparation of a medicament for use in the treatment of a thromboembolicdisorder or cancer or rheumatoid arthritis in an animal. Preferably, thedisorder is a thromboembolic disorder.

In a seventh aspect, this invention is directed to an intermediate ofFormula II:

wherein R¹, R², R³, R^(x), R^(y), and R^(z) are as defined in theirbroadest terms for compounds of Formula I herein.

In an eighth aspect, this invention is directed to a process ofpreparing a compound of Formula I where X¹ is —N— comprising reacting acompound of Formula II with a compound of Formula III:

where R¹³ is hydrogen;

optionally modifying any of the R¹, R², R³, R^(x), R^(y), R^(z), and R¹³groups;

optionally isolating individual isomers;

optionally preparing an acid addition salt; and

optionally preparing a free base.

In a ninth aspect, this invention is directed to a process of preparinga compound of Formula I where X¹ is —CH— and R¹³ is hydrogen, comprisingreacting a compound of Formula IV:

where X², X³, X⁴ are as defined in the Summary of the Invention and PG¹is a suitable amino protecting group;

with a compound of Formula V

where R¹, R², R³, R^(x), R^(y), and R^(z) are as defined in the Summaryof the Invention and PG is a suitable hydroxy protecting group; to givea compound of Formula VI:

optionally removing the amino and/or hydroxy protecting group;

converting the cyano to a carbamimidoyl group;

optionally removing the amino and/or hydroxy protecting group;

optionally modifying any of the R¹, R², R³, R^(x), R^(y), R^(z), and R¹³groups;

optionally isolating individual isomers;

optionally preparing an acid addition salt, and

optionally preparing a free base.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS

The following terms, as used in the present specification and claims,are intended to have the meanings as defined below, unless indicatedotherwise or used in naming a compound.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl (including all isomeric forms), pentyl (including allisomeric forms), and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms e.g., methylene, ethylene, propylene,1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

“Alkenylene” means a linear divalent hydrocarbon radical of two to sixcarbon atoms or a branched saturated divalent hydrocarbon radical ofthree to six carbon atoms containing one or two double bonds e.g.,ethenylene, propenylene, 2-methylpropenylene, and the like.

“Alkylthio” means a radical —SR where R is alkyl as defined above, e.g.,methylthio, ethylthio, propylthio (including all isomeric forms),butylthio (including all isomeric forms), and the like.

“Amino” means the radical —NRR′ where R and R′ are independentlyhydrogen, alkyl, or —COR^(a) where R^(a) is alkyl, e.g., —NH₂,methylaminoethyl, 1,3-diaminopropyl, acetylaminopropyl, and the like.

“Acyl” means a radical —COR′ where R′ is alkyl, alkoxy, haloalkyl,aminoalkyl, hydroxyalkyl, or alkoxyalkyl as defined herein, e.g.,acetyl, trifluoroacetyl, hydroxymethylcarbonyl, and the like.

“Aminosulfonyl” or “sulfamoyl” means a radical —SO₂NH₂.

“Alkylaminosulfonyl” means a radical —SO₂NHR where R is alkyl as definedabove, e.g., methylaminosulfonyl, ethylamino-sulfonyl, and the like.

“Alkylsulfonyl” means a radical —SO₂R where R is alkyl as defined above,e.g., methylsulfonyl, ethylsulfonyl, n- or iso-propylsulfonyl, and thelike.

“Alkylsulfonylalkyl” means a radical -alkylene)-SO₂R where R is alkyl asdefined above, e.g., methylsulfonylmethyl, ethylsulfonylmethyl, n- oriso-propylsulfonylethyl, and the like.

“Alkylsulfonylamino” means a radical —NHSO₂R where R is alkyl as definedabove, e.g., methylsulfonylamino, ethylsulfonylamino, n- orfso-propylsulfonylamino, and the like.

“Alkylsulfonylaminoalkyl” means a radical -(alkylene)-NHSO₂R where R isalkyl as defined above, e.g., methylsulfonylaminomethyl,ethylsulfonylaminomethyl, n- or iso-propylsulfonylaminoethyl, and thelike.

“Alkoxysulfonylamino” means a radical —NHSO₂R where R is alkoxy asdefined herein, e.g., methoxysulfonylamino, ethoxysulfonylamino, and thelike.

“Alkoxysulfonylaminoalkyl” means a radical -(alkylene)-NHSO₂R where R isalkoxy as defined herein, e.g., methoxysulfonylaminomethyl,ethoxysulfonylaminomethyl, and the like.

“Alkoxy” means a radical —OR where R is alkyl as defined above, e.g.,methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, andthe like.

“Alkoxycarbonyl” means a radical —COOR where R is alkyl as definedabove, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Alkoxycarbonylalkyl” means a radical -(alkylene)-COOR where R is alkylas defined above, e.g., methoxycarbonylmethyl, ethoxycarbonylmethyl, andthe like.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with at least one alkoxy group, preferablyone or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-,2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

“Aminoalkyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with at least one, preferably one or two, —NRR′where R and R′ are independently hydrogen, alkyl, or —COR^(a) whereR^(a) is alkyl, e.g., aminomethyl, methylaminoethyl, 1,3-diaminopropyl,acetylaminopropyl, and the like.

“Aminocarboxyalkyl” means a linear monovalent hydrocarbon radical of oneto six carbon atoms or a branched monovalent hydrocarbon radical ofthree to six carbons substituted with one —NRR′ and —COOH where R and R′are independently hydrogen, alkyl, or —COR^(a) where R^(a) is alkyl,e.g., 1-amino-1-carboxypentyl, and the like.

“Aminocarbonylcarboxyalkyl” means a linear monovalent hydrocarbonradical of one to six carbon atoms or a branched monovalent hydrocarbonradical of three to six carbons substituted with one —CONRR′ and —COOHwhere R and R′ are independently hydrogen, alkyl, or —COR^(a) whereR^(a) is alkyl, e.g., 1-aminocarbonyl-1-carboxypentyl, and the like.

“Aminocarbonylalkyl” means a linear monovalent hydrocarbon radical ofone to six carbon atoms or a branched monovalent hydrocarbon radical ofthree to six carbons substituted with one or two —CONRR′ where R and R′are independently hydrogen, alkyl, or —COR^(a) where R^(a) is alkyl,e.g., aminocarbonylmethyl, methylaminocarbonylmethyl,acetylaminocarbonylpropyl, and the like.

“Alkoxyalkyloxy” means a radical —OR where R is alkoxyalkyl, as definedabove, e.g., 2-methoxyethyloxy, 1-, 2-, or 3-methoxypropyloxy,2-ethoxyethyloxy, and the like.

“Aminoallyloxy” means a radical —OR where R is aminoalkyl, as definedabove, e.g., 2-aminoethyloxy, 1-, 2-, or 3-methylaminopropyloxy, and thelike.

“Aminocarbonyl” or “carbamoyl” means a radical —CONH₂.

“Aminocarbonylalkyloxy” means a radical —O-alkylene-CONRR″ where R andR′ are independently hydrogen or alkyl, as defined above, e.g.,2-aminocarbonylethyloxy, aminocarbonylmethyloxy, and the like.

“Aminocarbonylalkyl” means a radical -(alkylene)-CONH₂, e.g.,aminocarbonylmethyl, aminocarbonylethyl, 1-, 2-, or3-aminocarbonylpropyl, and the like.

“Alkylureido” means a radical —NRCONHR′ where R is hydrogen or alkyl andR′ is alkyl, e.g., methylureidomethyl, and the like.

“Alkylureidoalkyl” means a radical -(alkylene)-NRCONHR′ where R ishydrogen or alkyl and R′ is alkyl, e.g., methylureidomethyl, and thelike.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 12 ring atoms, and optionally substituted independentlywith one or more substituents, preferably one, two, or threesubstituents, selected from alkyl, haloalkyl, alkoxy, alkylthio, halo,nitro, —COR (where R is alkyl), cyano, amino, alkylamino, dialkylamino,hydroxy, carboxy, or —COOR where R is alkyl. Representative examplesinclude, but are not limited to, phenyl, biphenyl, 1-naphthyl, and2-naphthyl and the derivatives thereof.

“Arylsulfonyl” means a radical —SO₂R where R is aryl as defined above,e.g., phenylsulfonyl, and the like.

“Aralkyl” means a radical -(alkylene)-R where R is an aryl group asdefined above e.g., benzyl, phenylethyl,3-3-chlorophenyl)-2-methylpentyl, and the like.

“Alkoxycarbamimidoyl” means a radical —C(═NH)NHOR or —C(═NOR)NH₂ where Ris alkyl as defined above, e.g., methoxycarbamimidoyl.

“Cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical ofthree to six carbon atoms, e.g., cyclopropyl, cyclobutyl, and the like,preferably cyclopropyl.

“Carboxyalkyl” means a radical -(alkylene)-COOH, e.g., carboxymethyl,carboxyethyl, 1-, 2-, or 3-carboxypropyl, and the like.

“Carboxyalkyloxy” means a radical —O-(alkylene)-COOH, e.g.,carboxymethyloxy, carboxyethyloxy, and the like.

“carbamimidoyl” means a radical —C(═NH)NH₂, or a protected derivativethereof.

“Cyanoalkyl” means a radical -(alkylene)-CN, e.g., cyanomethyl,cyanoethyl, cyanopropyl, and the like.

“Dialkylaminosulfonyl” means a radical —SO₂NRR′ where R and R′ areindependently alkyl as defined above, e.g., dimethylaminosulfonyl,methylethylamino-sulfonyl, and the like.

“Dialkylureido” means a radical —NRCONR′R″ where R is hydrogen or alkyland R′ and R″ are independently alkyl, e.g., dimethylureido, and thelike.

“Dialkylureidoalkyl” means a radical -(alkylene)-NRCONR′R″ where R ishydrogen or alkyl and R′ and R″ are independently alkyl, e.g.,dimethylureidomethyl, and the like.

“Guanidinoalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with at least one, preferably one or two,—NRC(NRR′)NRR′ where R and R′ are independently hydrogen, alkyl, or—COR^(a) where R^(a) is alkyl, e.g., guanidinomethyl,N′-methylaminoethyl, 2-(N′,N′, N″, N″-tetramethyl-guanidino)-ethyl, andthe like.

“Halo” means fluoro, chloro, bromo, and iodo, preferably fluoro orchloro.

“Haloalkyl” means alkyl substituted with one or more halogen atoms,preferably one to three halogen atoms, preferably fluorine or chlorine,including those substituted with different halogens, e.g., —CH₂Cl, —CF₃,—CHF₂, and the like.

“Haloalkoxy” means a radical —OR where R is haloalkyl as defined above,e.g., —OCH₂Cl, —OCF₃, —OCHF₂, and the like.

“Haloalkylthio” means a radial —SR where R is haloalkyl as definedabove.

“Haloalkylsulfonyl” means a radial —SO₂R where R is haloalkyl as definedabove.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with one to five hydroxy groups, providedthat if two hydroxy groups are present they are not both on the samecarbon atom. Representative examples include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

“Hydroxyalkyloxy” means a radical —OR where R is hydroxyalkyl as definedabove, e.g., 2-hydroxyethyloxy, 3-hydroxypropyloxy, and the like.

“Hydroxyalkylcarbonyl” means a radical —COR where R is hydroxyalkyl asdefined above. Respresentative examples include, but are not limited to,hydroxymethylcarbonyl, 2-hydroxyethylcarbonyl, and the like.

“Hydroxyalkoxyalkylaminocarbonyl” means a radical—CONH-(alkylene)-O-(alkylene)OH where alkylene is as defined above,e.g., —CONH—(CH₂)₂—O—(CH₂)₂OH and the like.

“Heterocycloalkyl” means a saturated or unsaturated monovalent cyclicgroup of 3 to 8 ring atoms in which one or two ring atoms areheteroatoms selected from N, O, or S(O)n, where n is an integer from 0to 2, the remaining ring atoms being C. The heterocycloalkyl ring may beoptionally substituted with one or more substituents, preferably one ortwo substituents, independently selected from alkyl, aryl, heteroaryl,aralkyl, 3,5,6-trihydroxy-2-hydroxymethyl-tetrahydropyran-3-yl,4,5-dihydroxy-2-hydroxymthyl-6-(4,5,6-trihydroxy-2-hydroxymthyl-tetrahydro-pyran-3-yloxy)-tetrahydro-pyran-3-yl,heteroaralkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, aminoalkyl, guanidinoalkyl, halo, cyano, carboxy, —COOR(where R is alkyl as define above), or —CONR^(a)R^(b) (where R^(a) andR^(b) are independently hydrogen or alkyl), or a protected derivativethereof. More specifically the term heterocycloalkyl includes, but isnot limited to, pyrrolidino, piperidino, morpholino, piperazino,tetrahydropyranyl, and thiomorpholino.

“Heterocycloalkylcarbonyl” means a radical —COR where R isheterocycloalkyl as defined above. More specifically the termheterocycloalkylcarbonyl includes, but is not limited to,1-pyrrolidinocarbonyl, 1-piperidinocarbonyl, 4-morpholinocarbonyl,1-piperazinocarbonyl, 2-tetrahydropyranylcarbonyl, and4-thiomorpholinocarbonyl, and the derivatives thereof.

“Heterocycloalkylcarbonylalkyl” means a radical -(alkylene)-COR where Ris heterocycloalkyl as defined above. More specifically the termheterocycloalkylcarbonyl includes, but is not limited to,1-pyrrolidinocarbonylmethyl, 1-piperidinocarbonylmethyl,4-morpholinocarbonylethyl, 1-piperazinocarbonylmethyl, and thederivatives thereof.

“Heterocycloalkylalkyl” means a radical -alkylene)-R where R isheterocycloalkyl as defined above. More specifically the termheterocycloalkylalkyl includes, but is not limited to,pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 2-morpholin-1-ylethyl,piperazin-1-ylethyl, and the derivatives thereof.

“Heterocycloalkylalkylaminocarbonyl” means a radical —CONH-(alkylene)-Rwhere R is heterocycloalkyl as defined above. More specifically the termheterocycloalkylalkylamino-carbonyl includes, but is not limited to,1-pyrrolidinoethyl-aminocarbonyl, 1-piperidinoethyl-aminocarbonyl,4-morpholinoethylcarbonyl, 1-piperazinoethylarninocarbonyl, and4-thiomorpholinopropylaminocarbonyl, and the derivatives thereof.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms containing one or more, preferably one or two ringheteroatoms selected from N, O, or S, the remaining ring atoms beingcarbon. The heteroaryl ring is optionally substituted with one or moresubstituents, preferably one or two substituents, independently selectedfrom alkyl, haloalkyl, alkoxy, alkylthio, aminoalkyl, guanidinoalkyl,halo, nitro, cyano, amino, alkyl or dialkylamino, hydroxy, carboxy, or—COOR where R is alkyl as define above. More specifically the termheteroaryl includes, but is not limited to, pyridyl, pyrrolyl,imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazine, pyrimidine,pyradizine, oxazole, isooxazolyl, benzoxazole, quinoline, isoquinoline,benzopyranyl, and thiazolyl.

“Heteroarylsulfonyl” means a radical —SO₂R where R is heteroaryl asdefined above, e.g., pyridylsulfonyl, furanylsulfonyl, and the like.

“Heteroaralkyl” means a radical -(alkylene)-R where R is a heteroarylgroup as defined above e.g., pyridylmethyl, furanylnethyl,indolylmethyl, pyrimidinylmethyl, and the like.

“Heterocycloamino” means a saturated or unsaturated monovalent cyclicgroup of 3 to 8 ring atoms in which one or two ring atoms areheteroatoms selected from N, O, or S(O)n, where n is an integer from 0to 2, the remaining ring atoms being C provided that at least one of theheteroatom is nitrogen and wherein one or two carbon atoms areoptionally replace by a carbonyl group. The heterocycloamino ring may beoptionally substituted with one or more substituents, preferably one ortwo substituents, independently selected from alkyl, hydroxy,hydroxyalkyl, alkoxy, alkoxyallyl, aminoalkyl, guanidinoalkyl, halo,haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, halo,cyano, carboxy, —CONR^(a)R^(b) (where R^(a) and R^(b) are independentlyhydrogen or alkyl), or —COOR where R is alkyl as define above. Morespecifically the term heterocycloamino includes, but is not limited to,pyrrolidino, piperidino, piperazino, and thiomorpholino, and thederivatives thereof.

“Hydroxycarbamimidoyl” means a radical —C(═NI)NHOH or —C(═NOH)NH₂.

The present invention also includes the prodrugs of compounds of FormulaI. The term prodrug is intended to represent covalently bonded carriers,which are capable of releasing the active ingredient of Formula I, whenthe prodrug is administered to a mammalian subject. Release of theactive ingredient occurs in vivo. Prodrugs can be prepared by techniquesknown to one skilled in the art. These techniques generally modifyappropriate functional groups in a given compound. These modifiedfunctional groups however regenerate original functional groups byroutine manipulation or in vivo. Prodrugs of compounds of Formula Iinclude compounds wherein a hydroxy, carbamimidoyl, guanidino, amino,carboxylic, or a similar group is modified. Examples of prodrugsinclude, but are not limited to esters (e.g., acetate, formate, andbenzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) ofhydroxy functional groups in compounds of Formula I and the like.Prodrugs of compounds of Formula I are also within the scope of thisinvention.

The present invention also includes (derivatives and protectedderivatives of compounds of Formula I. For example, when compounds ofFormula I contain an oxidizable nitrogen atom (e.g., when a compound ofFormula I contains a pyridine, amino, alkylamino, piperidino,piperazino, morpholino, or dialkylamino group), the nitrogen atom can beconverted to an N-oxide by methods well known in the art.

Also when compounds of Formula I contain groups such as hydroxy,carboxy, carbonyl, thiol or any group containing a nitrogen atom(s),these groups can be protected with a suitable protecting groups. Acomprehensive list of suitable protective groups can be found in T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc.1981, the disclosure of which is incorporated herein by reference in itsentirety. The protected derivatives of compounds of Formula I can beprepared by methods well known in the art.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. It is understood that thepharmaceutically acceptable salts are non-toxic. Additional informationon suitable pharmaceutically acceptable salts can be found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, which is incorporated herein by reference.

The compounds of the present invention may have asymmetric centers.Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of materials. Many geometric isomers of olefins, C=Cdouble bonds, and the like can be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms. All chiral, enantiomeric,diastereomeric, racemic forms and all geometric isomeric forms of astructure (representing a compound of Formula I) are intended, unlessthe specific stereochemistry or isomeric form is specifically indicated.

Certain compounds of Formula I exist in tautomeric equilibrium.Compounds of Formula I, which exist as tautomers are named, illustratedor otherwise described in this application as one possible tautomer.However, it is to be understood that all possible tautomers are meant tobe encompassed by such names, illustrations and descriptions and arewithin the scope of this invention. For example, in compound of FormulaI, the group —C(═NR¹³)NH₂ can tautomerize to —C(═NH)NHR¹³ group.Additionally, as used herein the terms alkyl includes all the possibleisomeric forms of said alkyl group albeit only a few examples are setforth. Furthermore, when the cyclic groups such as aryl, heteroaryl,heterocycloalkyl are substituted, they include all the positionalisomers albeit only a few examples are set forth.

“Oxoheterocycloalkyl” means a saturated or unsaturated (provided that itis not aromatic) monovalent cyclic group of 3 to 8 ring atoms in whichone or two ring atoms are heteroatoms selected from N, O, or S(O)n,where n is an integer from 0 to 2, the remaining ring atoms being Cwherein one or two of the carbon atoms is/are replaced with an oxo (C═O)group. The oxoheterocycloalkyl ring may be optionally substituted withone or more substituents, preferably one or two substituents,independently selected from alkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, haloalkyl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl,aminoalkyl, guanidinoalkyl, alkoxy, cyano, carboxy, or —COOR where R isalkyl as define above. More specifically the term heterocycloalkyl;includes, but is not limited to, 2 or 3-oxopyrrolidin-1-yl, 2, 3, or4-oxopiperidino, 3-oxomorpholino, 2-oxo-piperazino,2-oxotetrahydropyranyl, 3-oxothiomorpholino, 2-imidazolidone, and thederivatives thereof.

“Oxoheterocycloalkylalkyl” means a radical -(alkylene)-R where R is aoxoheterocycloalkylalkyl group as defined above e.g., More specificallythe term oxoheterocycloalkylalkyl; includes, but is not limited to, 2 or3-oxopyrrolidin-1-yl-(methyl, ethyl, or propyl), 2, 3, or4-oxopiperidin-1-yl-(methyl, ethyl, or propyl),3-oxomorpholin4yl-(methyl, ethyl, or propyl),2-oxopiperazin-1-yl-(methyl, ethyl, or propyl),2-oxotetrahydro-pyran-3-yl-methyl, ethyl, or propyl),3-oxothiomorpholin-4-yl-methyl, ethyl, or propyl),2-imidazolidon-1-yl-(methyl, ethyl, or propyl), and the derivativesthereof.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocycloalkyl group optionallymono- or di-substituted with an alkyl group” means that the alkyl maybut need not be present, and the description includes situations wherethe heterocycloalkyl group is mono- or disubstituted with an alkyl groupand situations where the heterocycloalkyl group is not substituted withthe alkyl group.

A “pharmaceutically acceptable carrier or excipient” means a carrier oran excipient that is useful in preparing a pharmaceutical compositionthat is generally safe, non-toxic and neither biologically nor otherwiseundesirable, and includes a carrier or an excipient that is acceptablefor veterinary use as well as human pharmaceutical use. “Apharmaceutically acceptable carrier/excipient” as used in thespecification and claims includes both one and more than one suchexcipient.

“Phosphoalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with at least one, preferably one or two,—P(O)(OH)₂, e.g., phosphomethyl, 2-phosphoethyl,1-methyl-2-phosphoethyl, 1,3-diphosphopropyl, and the like.

“Sulfoalkyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with at least one, preferably one or two, —SOOH,e.g., sulfomethyl, 2-sulfoethyl, 1-methyl-2-sulfoethyl,1,3-disulfopropyl, and the like.

“Treating” or “treatment” of a disease includes:

-   (1) preventing the disease, i.e. causing the clinical symptoms of    the disease not to develop in a mammal that may be exposed to or    predisposed to the disease but does not yet experience or display    symptoms of the disease,-   (2) inhibiting the disease, i.e., arresting or reducing the    development of the disease or its clinical symptoms, or-   (3) relieving the disease, i.e., causing regression of the disease    or its clinical symptoms.

A “therapeutically effective amount” means the amount of a compound ofFormula I that, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

“Thioureido” means a radical —NRC(S)NR′R″ where R, R′, and R″ areindependently hydrogen or alkyl.

“Thioureidoalkyl” means a radical -(alkylene)-NRC(S)NR′R″ where alkyleneis as defined above. Representative examples include but are not limitedto thioureidomethyl, thioureidoethyl, and the like.

“Trimethylammonioalkyl” means a linear monovalent hydrocarbon radical ofone to six carbon atoms or a branched monovalent hydrocarbon radical ofthree to six carbons substituted with one —N⁺(CH₃), e.g.,trimethylammoniomethyl, 2-ammonioethyl, and the like.

“Ureido” means a radical —NHCONH₂.

“Ureidoalkyl” means a radical -(alkylene)-NHCONH₂ where alkylene is asdefined above. Representative examples include but are not limited toureidomethyl, ureidoethyl, and the like.

The compounds of the present invention are numbered as follows:

Representative compounds of Formula I where R¹, R² and R^(y) arehydrogen; X¹ is —N—, X², X³, and X⁴ are carbon are disclosed in Table Ibelow. TABLE I

Cpd. # R³ Position, R^(x) Position, R^(z)  1 —F 2′, —OH 5′, —CH₂NHCONH₂ 2

2′, —OH 5′, —F  3

2′, —OH 5′, —F  4

2′, —OH 5′, —F  5

2′, —OH 5′, —F  6

2′, —OH 5′, —F  7

2′, —OH 5′, —F  8

H 3′, —SO₂NH₂  9 —CON(CH₃)₂ H 3′, —SO₂NH₂  10 —H 2′, —OH 5′, —CH₂NHCONH₂ 11 —H 2′, —OH 5′, —CH₂CONH₂  12 —SO₂NH₂ 2′, —OH 5′, —CH₂NHCONH₂  13tetrazol-5-yl 2′, —OH 5′, —CH₂NHCONH₂  14 —H H 3′, —SO₂NH₂  15—CONHSO₂—(CH₂)₃CH₃ H 3′, —SO₂NH₂  16

2′, —OH 5′, —F  17

2′, —OH 5′, —F  18

2′, —OH 5′, —F  19 —H 2′, —OCH₃ 5′, —F  20 —H 2′, —OH 5′, —F  21 —CH₂CN2′, —OH 5′, —CH₂NHCONH₂  22

2′, —OH 5′, —F  23 —CH₂CONHCH₃ 2′, —OH 5′, —CH₂NHCONH₂  24

2′, —OH 5′, —F  25 —CON(CH₃)₂ 2′, —OH 5′, —F  26 tetrazol-5-yl H 5′,—CH₂NHCONHC(CH₃)₃  27 tetrazol-5-ylmethyl 2′, —OH 5′, —CH₂NHCONH₂  28—(CH₂)₂CN 2′, —OH 5′, —CH₂NHCONH₂  29

2′, —OH 5′, —F  30

2′, —OH 5′, —F  31 —SO₂NHCOCH₃ H 3′, —SO₂NH₂  32 —SO₂NHCOCH₃ H 3′, —NH₂ 33

2′, OH 5′, —F  34

2′, OH 5′, —F  35

2′, OH 5′, —F  36

2′, OH 5′, —F  37

2′, OH 5′, —F  38

2′, OH 5′, —F  39

2′, OH 5′, —F  40

2′, OH 5′, —F  41

2′, OH 5′, —F  42 tetrazol-5-yl 2′, OH 5′, —F  43

2′, OH 5′, —F  44 —CH₂CON(CH₂CH₂OCH₃)₂ 2′, OH 5′, —F  45—CH₂CONH(CH₂)₂OH 2′, OH 5′, —F  46 —CH₂CON(CH₂CH₂OH)₂ 2′, OH 5′, —F  47—CH₂CONH(CH₂)₂OCH₃ 2′, OH 5′, —F  48 —CH₂CON(CH₃)₂ 2′, OH 5′, —F  49—CH₂CONH(CH₂)₂N(CH₃)₂ 2′, OH 5′, —F  50 tetrazol-5-ylmethyl H 3′,—SO₂NH₂  51 —SO₂NH₂ H 3′, —SO₂NH₂  52 —CH₃ H 3′, —SO₂NH₂  53 —CH₂CN H3′, —SO₂NH₂  54 tetrazol-5-yl H 3′, —SO₂NH₂  55 —Cl 2′, —OH 5′,—CH₂NHCONH₂  56 tetrazol-5-yl H 5′, —CH₂NHCONH₂  57 tetrazol-5-ylmethyl2′, —OH 5′, —CH₂NH₂  58

2′, —OH 5′, —F  59

H 3′, —SO₂NH₂  60

H 3′, —SO₂NH₂  61 —CH₃ 2′, —OH 5′, —CH₂NHCONH₂  62 —F 2′, —OH 5′,—CH₂NHCONH₂  63 —Cl 2′, —OH

 64 —CH₃ 3′, —Br 4′, —OH  65 —CH₃ 2′, —OH 5′, —CH₂COOH  66 —CH₃ 2′, —OH5′, —CH₂CONH₂  67 —H 2′, —OH 5′, —CH₂NHCOCH₃  68 —H 2′, —OH 5′,—CH₂CONHCH₃  69

2′, —OH 5′, —F  70

2′, —OH 5′, —F  71 —CON(CH₃)(CH₂CONH₂) 2′, —OH 5′, —F  72

2′, —OH 5′, —F  73

2′, —OH 5′, —F  74

2′, —OH 5′, —F  75

2′, —OH 5′, —F  76

2′, —OH 5′, —F  77 —CH₂CONHCH(CH₂OH)CH₂OH 2′, —OH 5′, —F  78 —H 2′, —OH5′, —SO₂NH₂  79 —H 2′, —OH 5′, —CH₂NHCOCH₂OH  80 —Cl 2′, —OH 5′, —CONH₂ 81 —H 2′, —OH 5′, —CONH₂  82 —CH₃ 2′, —OH 5′, —CH₂NHCONH₂  83 —H 2′,—OH 5′, —CH₂NHSO₂CH₃  84 —H 2′, —OH 5′, —CH₂CON(CH₃)₂  85 —Cl 2′, —OH5′, —CH₂CONH₂  86 —F 2′, —OH 5′, —CH₂COOH  87 —F 2′, —OH 5′, —CH₂CONH₂ 88 —CF₃ 2′, —OH 5′, —CONH₂  89 —H 2′, —OH 5′, —CH₂NHCOOCH₃  90 —H 2′,—F 5′, —CH₂NHCONH₂  91 —H 2′, —OH 5′, —CH₂NHCON(CH₃)₂  92 —OCH₃ 2′, —OH5′, —CH₂NHCOCH₃  93 —OCF₃ 2′, —OH 5′, —CH₂COOH  94 —SO₂N(CH₃)₂ 2′, —OH5′, —CH₂NHCONH₂  95 —H 2′, —OH

 96 —H 2′, —OH 5′, —CH₂CONH(CH₂)₂OH  97 —H 2′, —OH

 98

2′, —OH 5′, —CH₂NHCONH₂  99

2′, —OH 5′, —CH₂NHCONH₂ 101 —Cl 2′, —OH

102 —H 2′, —OH 5′, —CH₂OH 103 —OCH₃ 2′, —OH 5′, —CH₂COOH 104 —F 2′, —OH5′, —CH₂NHC(O)CH₂OH 105 —CH₂C(O)NH(CH₂)₂N⁺(CH₃)₃ 2′, —OH 5′, —SO₂NH₂ 106—C(O)N(CH₃)CH₂C(O)NH₂ 2′, —OH 5′, —SO₂NH₂ 107

2′, —OH 5′, —SO₂NH₂ 108

2′, —OH 5′, —SO₂NH₂ 109

2′, —OH 5′, —SO₂NH₂ 110

2′, —OH 5′, —SO₂NH₂ 111 —C(O)NH(CH₂)₂SO₃H 2′, —OH 5′, —SO₂NH₂ 112—CH₂C(O)NH(CH₂)₄CH(NH₂)C(O)OH 2′, —OH 5′, —SO₂NH₂ 113

2′, —OH 5′, —SO₂NH₂ 114

2′, —OH —H 115

H 3′, —NO₂ 116

H 3′, —NO₂ 117

H 3′, —NH₂ 118

H 3′, —NH₂ 119

H 3′, —NHC(O)NH₂ 120

H 3′, —NH₂ 121

2′, —OH 5′, —SO₂NH₂ 122 —CH₂C(O)N(CH₂COOH)₂ 2′, —OH 5′, —SO₂NH₂ 123

2′, —OH 5′, —SO₂NH₂ 124

2′, —OH 5′, —SO₂NH₂ 125

2′, —OH 5′, —SO₂NH₂ 126 —CH₂C(O)NH₂ 2′, —OH 5′, —SO₂NH₂ 127—CH₂C(O)N(CH₃)₂ 2′, —OH 5′, —SO₂NH₂ 128 —CH₂C(O)NHCH(CH₂OH)₂ 2′, —OH 5′,—SO₂NH₂ 129 —CH₂C(O)NHCH₂COOH 2′, —OH 5′, —SO₂NH₂ 130 —CH₂C(O)NHCH₂CONH₂2′, —OH 5′, —SO₂NH₂ 131 —CH₂C(O)NHCH₂CH₂N(CH₃)₂ 2′, —OH 5′, —SO₂NH₂ 132—CH₂C(O)NHCH₂CH₂CH₂N(CH₃)₂ 2′, —OH 5′, —SO₂NH₂ 133 —CH₂C(O)NHCH₂CH₂COOH2′, —OH 5′, —SO₂NH₂ 134

2′, —OH 5′, —SO₂NH₂ 135

2′, —OH 5′, —SO₂NH₂ 136

2′, —OH 5′, —SO₂NH₂ 137

2′, —OH 5′, —SO₂NH₂ 138

2′, —OH 5′, —SO₂NH₂ 139 —CH₂C(O)NHCH₃ 2′, —OH 5′, —SO₂NH₂ 140

2′, —OH 5′, —SO₂NH₂ 141

2′, —OH 5′, —SO₂NH₂ 142

2′, —OH 5′, —SO₂NH₂ 143

2′, —OH 5′, —SO₂NH₂ 144

2′, —OH 5′, —SO₂NH₂ 145

2′, —OH 5′, —SO₂NH₂ 146 —C(CH₃)₂C(O)N(CH₂COOH)₂ 2′, —OH 5′, —SO₂NH₂ 147—C(CH₃)₂C(O)NHCH(COOH)CH₂COOH 2′, —OH 5′, —SO₂NH₂ 148

2′, —OH 5′, —SO₂NH₂ 149

2′, —OH 5′, —SO₂NH₂ 150 —C(CH₃)₂C(O)NH₂ 2′, —OH 5′, —SO₂NH₂ 151—C(CH₃)₂C(O)N(CH₃)₂ 2′, —OH 5′, —SO₂NH₂ 152 —C(CH₃)₂C(O)NHCH(CH₂OH)₂ 2′,—OH 5′, —SO₂NH₂ 153 —C(CH₃)₂C(O)NHCH₂COOH 2′, —OH 5′, —SO₂NH₂ 154—C(CH₃)₂C(O)NHCH₂CONH₂ 2′, —OH 5′, —SO₂NH₂ 155—C(CH₃)₂C(O)NHCH₂CH₂N(CH₃)₂ 2′, —OH 5′, —SO₂NH₂ 156—C(CH₃)₂C(O)NHCH₂CH₂CH₂N(CH₃)₂ 2′, —OH 5′, —SO₂NH₂ 157—C(CH₃)₂C(O)NHCH₂CH₂COOH 2′, —OH 5′, —SO₂NH₂ 158

2′, —OH 5′, —SO₂NH₂ 159

2′, —OH 5′, —SO₂NH₂ 160

2′, —OH 5′, —SO₂NH₂ 161

2′, —OH 5′, —SO₂NH₂ 162

2′, —OH 5′, —SO₂NH₂ 163 —C(CH₃)₂C(O)NHCH₃ 2′, —OH 5′, —SO₂NH₂ 164

2′, —OH 5′, —SO₂NH₂ 165

2′, —OH 5′, —SO₂NH₂ 166

2′, —OH 5′, —SO₂NH₂ 167

2′, —OH 5′, —SO₂NH₂ 168

2′, —OH 5′, —SO₂NH₂ 169

2′, —OH 5′, —CH₂NHC(O)NH₂ 170 —C(CH₃)₂C(O)N(CH₂COOH)₂ 2′, —OH 5′,—CH₂NHC(O)NH₂ 171 —C(CH₃)₂C(O)NHCH(COOH)CH₂COOH 2′, —OH 5′,—CH₂NHC(O)NH₂ 172

2′, —OH 5′, —CH₂NHC(O)NH₂ 173

2′, —OH 5′, —CH₂NHC(O)NH₂ 174 —C(CH₃)₂C(O)NH₂ 2′, —OH 5′, —CH₂NHC(O)NH₂175 —C(CH₃)₂C(O)N(CH₃)₂ 2′, —OH 5′, —CH₂NHC(O)NH₂ 176—C(CH₃)₂C(O)NHCH(CH₂OH)₂ 2′, —OH 5′, —CH₂NHC(O)NH₂ 177—C(CH₃)₂C(O)NHCH₂COOH 2′, —OH 5′, —CH₂NHC(O)NH₂ 178—C(CH₃)₂C(O)NHCH₂CONH₂ 2′, —OH 5′, —CH₂NHC(O)NH₂ 179—C(CH₃)₂C(O)NHCH₂CH₂N(CH₃)₂ 2′, —OH 5′, —CH₂NHC(O)NH₂ 180—C(CH₃)₂C(O)NHCH₂CH₂CH₂N(CH₃)₂ 2′, —OH 5′, —CH₂NHC(O)NH₂ 181—C(CH₃)₂C(O)NHCH₂CH₂COOH 2′, —OH 5′, —CH₂NHC(O)NH₂ 182

2′, —OH 5′, —CH₂NHC(O)NH₂ 183

2′, —OH 5′, —CH₂NHC(O)NH₂ 184

2′, —OH 5′, —CH₂NHC(O)NH₂ 185

2′, —OH 5′, —CH₂NHC(O)NH₂ 186

2′, —OH 5′, —CH₂NHC(O)NH₂ 187 —C(CH₃)₂C(O)NHCH₃ 2′, —OH 5′,—CH₂NHC(O)NH₂ 188

2′, —OH 5′, —CH₂NHC(O)NH₂ 189

2′, —OH 5′, —CH₂NHC(O)NH₂ 190

2′, —OH 5′, —CH₂NHC(O)NH₂ 191

2′, —OH 5′, —CH₂NHC(O)NH₂ 192

2′, —OH 5′, —CH₂NHC(O)NH₂ 193

2′, —OH 5′, —SO₂NH₂ 194 —C(O)N(CH₂COOH)₂ 2′, —OH 5′, —SO₂NH₂ 195

2′, —OH 5′, —SO₂NH₂ 196

2′, —OH 5′, —SO₂NH₂ 197

2′, —OH 5′, —SO₂NH₂ 198 —C(O)NH₂ 2′, —OH 5′, —SO₂NH₂ 199 —C(O)N(CH₃)₂2′, —OH 5′, —SO₂NH₂ 200 —C(O)NHCH(CH₂OH)₂ 2′, —OH 5′, —SO₂NH₂ 201—C(O)NHCH₂COOH 2′, —OH 5′, —SO₂NH₂ 202 —C(O)NHCH₂CONH₂ 2′, —OH 5′,—SO₂NH₂ 203 —C(O)NHCH₂CH₂N(CH₃)₂ 2′, —OH 5′, —SO₂NH₂ 204—C(O)NHCH₂CH₂CH₂N(CH₃)₂ 2′, —OH 5′, —SO₂NH₂ 205 —C(O)NHCH₂CH₂COOH 2′,—OH 5′, —SO₂NH₂ 206

2′, —OH 5′, —SO₂NH₂ 207

2′, —OH 5′, —SO₂NH₂ 208

2′, —OH 5′, —SO₂NH₂ 209

2′, —OH 5′, —SO₂NH₂ 210

2′, —OH 5′, —SO₂NH₂ 211 —C(O)NHCH₃ 2′, —OH 5′, —SO₂NH₂ 212

2′, —OH 5′, —SO₂NH₂ 213

2′, —OH 5′, —SO₂NH₂ 214

2′, —OH 5′, —SO₂NH₂ 215

2′, —OH 5′, —SO₂NH₂ 216

2′, —OH 5′, —SO₂NH₂ 217 —C(O)N(CH₂CH₂OH) 2′, —OH 5′, —SO₂NH₂ 218—C(O)NHCH₂CH₂N⁺(CH₃)₃ 2′, —OH 5′, —SO₂NH₂ 219

2′, —OH 5′, —SO₂NH₂ 220 —C(O)NHCH₂CH₂CH₂CH₂CH(NH₂)COOH 2′, —OH 5′,—SO₂NH₂ 221 —C(O)NHOH 2′, —OH 5′, —SO₂NH₂ 222 —C(O)N(CH₃)₂ 2′, —OH 5′,—SO₂NH₂ 223 —C(O)NH₂ 2′, —OH 5′, —SO₂NH₂ 224

2′, —OH 5′, —SO₂NH₂ 225

2′, —OH 5′, —SO₂NH₂ 226

2′, —OH 5′, —SO₂NH₂ 228

2′, —OH 5′, —SO₂NH₂ 229 —C(O)NHCH₃ 2′, —OH 5′, —SO₂NH₂ 230

2′, —OH 5′, —SO₂NH₂ 231

2′, —OH 5′, —SO₂NH₂ 232

2′, —OH 5′, —SO₂NH₂ 233

2′, —OH 5′, —SO₂NH₂ 234 —CH₂C(O)NHCH₂CH₂S(O)₂OH 2′, —OH 5′, —SO₂NH₂ 235

2′, —OH 5′, —SO₂NH₂ 236 —CH₃ H 4′, —OH 237

2′, —OH 5′, —F 238 —C(CH₃)₂C(O)NH₂ 2′, —OH 5′, —CH₂NHC(O)NH₂

Representative compounds of Formula I where R¹, R² and R^(y) arehydrogen; X² is —N—, X¹, X³, and X⁴ are carbon are disclosed in Table IIbelow. TABLE II

Cpd. # R³ Position, R^(x) Position, R^(z) 239 —H 2′, —OH 5′, CONH₂ 240—H 2′, —OH 5′, —NHCONH₂

The compounds of Formula I and the intermediates and starting materialsused in their preparation are named generally by AutoNom 4.0 (BeilsteinInformation Systems, Inc.).

Preferred Embodiments

While the broadest definition of this invention is set forth in theSummary of the Invention, certain compounds of Formula I are preferred.For example:(P) One Preferred Group of Compounds is Represented by the Formula Ia:

wherein:

R³ is hydrogen, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyanoalkyl,tetrazol-5-yl, tetrazol-5-ylalkyl, hydroxyalkylcarbonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, —NHSO₂R (where R is alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl or heterocycloalkylalkyl), —SO₂NHCOR⁶ (where R⁶ isalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, orheterocycloalkylalkyl), —CONR⁷R⁸ or —COCONR⁷R⁸ (where R⁷ is hydrogen,alkyl, alkoxyalkyl, carboxyalkyl, hydroxyalkyl or phosphonoalkyl and R⁸is hydrogen, alkyl, alkoxyalkyl, -(alkylene)-(OCH₂CH₂)_(n) R^(b) (wheren is an integer from 1 to 6 and R^(b) is hydrogen, alkyl, hydroxy,alkoxy, amino or alkylcarbonylamino), aminoalkyl, aminocarbonylalkyl,aminocarbonylcarboxyalkyl, aminocarboxyalkyl, carboxyalkyl,hydroxyalkyl, phosphonoalkyl, sulfoalkyl, trimethylammonioalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl or hetereocycloalkylalkyl or R⁷ andR⁸ together with the nitrogen atom to which they are attached formheterocycloalkylamino), -alkylene)-CONR⁹R¹⁰ (where R⁹ is hydrogen,alkyl, alkoxyalkyl, carboxyalkyl, hydroxyalkyl or phosphonoalkyl and R¹⁰is hydrogen, alkyl, alkoxyalkyl, -(alkylene)-(OCH₂CH₂)_(n) R^(b) (wheren is an integer from 1 to 6 and R^(b) is hydrogen, alkyl, hydroxy,alkoxy, amino or alkylcarbonylamino), aminoalkyl, aminocarbonylalkyl,aminocarbonylcarboxyalkyl, aminocarboxyalkyl, carboxyalkyl,hydroxyalkyl, phosphonoalkyl, sulfoalkyl, trimethylammonioalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkylalkyl or R⁹ andR¹⁰ together with the nitrogen atom to which they are attached formheterocycloalkylamino), —CONHSO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclalkyl, or heterocycloalkylalkyl),or -(alkylene)—CONHSO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl),wherein any rings comprising R³ are optionally substituted with one tosix groups independently selected from hydroxy, hydroxyalkyl,alkoxyalkyl, carboxy, alkoxycarbonyl, aminoalkyl, guanidinoalkyl, alkylor —CONR^(a)R^(b) where R^(a) and R^(b) are independently hydrogen oralkyl; and

R^(z) is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio, halo,hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl,alkoxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy, carboxyalkyloxy,aminocarbonylalkyloxy, haloalkoxy, carboxy, carboxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl,alkylsulfonylalkyl, arylsulfonyl, heteroarylsulfonyl, carbamimidoyl,hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino,alkylsulfonylaminoalkyl, alkoxysulfonylanino, alkoxysulfonylaminoalkyl,heterocycloalkylalkylaminocarbonyl, hydroxyalkoxyalkylaminocarbonyl,heterocycloalkylcarbonyl, heterocycloalkylcarbonylalkyl,heterocycloalkyl, heterocycloalkylalkyl, oxoheterocycloalkyl,oxoheterocycloalkylalkyl, heteroaryl, heteroaralkyl, ureido,alkylureido, dialkylureido, ureidoalkyl, alkylureidoalkyl,dialkylureidoalkyl, thioureido, thioureidoalkyl, —COR¹² (where R¹² isalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl),-(alkylene)-COR¹² (where R¹² is alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, or aminoalkyl), —CONR¹⁴R¹⁵ (where R¹⁴ is hydrogen or alkyland R¹⁵ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl,heteroaryl or heteroaralkyl or R¹⁴ and R¹⁵ together with the nitrogenatom to which they are attached from heterocycloamino),-(alkylene)-CONR¹⁶R¹⁷ (where R¹⁶ is hydrogen, alkyl or hydroxyalkyl andR¹⁷ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl,heteroaryl or heteroaralkyl or R¹⁴ and R¹⁵ together with the nitrogenatom to which they are attached from heterocycloamino), —NR¹⁸R¹⁹ (whereR¹⁸ is hydrogen or alkyl and R¹⁹ is hydrogen, alkyl, acyl, aryl,aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR²⁰R²¹ (where R²⁰is hydrogen, alkyl, or hydroxyalkyl and R²¹ is hydrogen, alkyl, acyl,alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl orheteroaralkyl), —SO₂NR²²R²³ (where R²² is hydrogen or alkyl and R²³ ishydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl or R²² andR²³ together with the nitrogen atom to which they are attached fromheterocycloamino), -(alkylene)-SO₂NR²⁴R²⁵ (where R²⁴ is hydrogen oralkyl and R²⁵ is hydrogen, alkyl, aryl, aralkyl, heteroaryl orheteroaralkyl or R²⁴ and R²⁵ together with the nitrogen atom to whichthey are attached from heterocycloamino), —NR²⁶SO₂NR²⁷R²⁸ (where R²⁶ andR²⁷ are independently hydrogen or alkyl, and R²⁸ is hydrogen, alkyl,aryl, aralkyl, heteroaryl or heteroaralkyl or R²⁷ and R²⁸ together withthe nitrogen atom to which they are attached from heterocycloamino),-alkylene)-NR²⁹SO₂NR³⁰R³¹ (where R²⁹ and R³⁰ are independently hydrogenor alkyl, and R³¹ is hydrogen, alkyl, aryl, aralkyl, heteroaryl orheteroaralkyl or R³⁰ and R³¹ together with the nitrogen atom to whichthey are attached from heterocycloamino), —CONH-(alkylene)-NR³²R³³ whereR³² is hydrogen or alkyl and R³³ is alkyl), or aralkyl; and

R¹³ is hydrogen, hydroxy, (C₁₋₁₀)alkoxy, —C(O)R³⁵ where R³⁵ is alkyl,aryl, haloalkyl, or cyanoalkyl, or —C(O)OR³⁶ where R³⁶ is alkyl,hydroxyalkyl, acyl, or haloalkyl; or a pharmaceutically acceptable saltthereof.

-   (a) Within the above group Ia, a more preferred group of compounds    is that wherein R³ is hydrogen.-   (b) Within the above group Ia, another more preferred group of    compounds is that wherein R³ is halo, preferably chloro or fluoro,    more preferably fluoro.-   (c) Within the above group Ia, another more preferred group of    compounds is that wherein R³ is —SO₂NHCOR⁶ where R⁶ is as defined in    its broadest terms in the Summary of the Invention. Preferably R⁶ is    alkyl, aralkyl, aryl, heteroaralkyl or heterocycloalkylalkyl. More    preferably R³ is aminosulfonyl, acetylaminosulfonyl,    2-phenyethylcarbonylaminosulfonyl, phenylcarbonylaminosulfonyl,    3-phenylpropylcarbonylaminosulfonyl, benzylcarbonylaminosulfonyl,    2-(3,4-dichlorophenyl)ethylcarbonylaminosulfonyl,    2-pyridin-3-ylethylcarbonylaminosulfonyl,    2-piperidin-3-ylethylcarbonylaminosulfonyl. Even more preferably R³    is acetylaminosulfonyl.-   (d) Within the above group Ia, yet another more preferred group of    compounds is that wherein R³ is —CONR⁷R⁸ (where R⁷ is hydrogen,    alkyl, hydroxyalkyl, or alkoxyalkyl and R⁸ is hydrogen, alkyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, aralkyl, heteroaryl,    heteroaralkyl, or hetereocycloalkylalkyl or R⁷ and R⁸ together with    the nitrogen atom to which they are attached form    heterocycloalkylamino), wherein any rings comprising R³ are    optionally substituted with one or two groups independently selected    from hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl, or    —CONR^(a)R^(b) where R^(a) and R^(b) are independently hydrogen or    alkyl. Preferably R⁷ is hydrogen or alkyl, and R⁸ is hydrogen,    alkyl, aralkyl, or heteroaralkyl, or R⁷ and R⁸ together with the    nitrogen atom to which they are attached form heterocycloalkylamino    optionally substituted with one or two groups independently selected    from hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl, or    —CONR^(a)R^(b) where R^(a) and R^(b) are independently hydrogen or    alkyl. More preferably, R⁷ and R⁸ together with the nitrogen atom to    which they are attached form optionally substituted    heterocycloalkylamino. Even more preferably, R³ is aminocarbonyl,    dimethylaminocarbonyl, 2-morpholin-4-ylethylaaminocarbonyl,    2-phenethylaaminocarbonyl, methylaminocarbonyl,    pyridin-2-ylmethylaminocarbonyl, furan-2-ylmethylaminocarbonyl,    2-pyridin4-ylethylaminocarbonyl, 2-pyridin-3-ylethylaminocarbonyl,    2-pyridin-2-ylethylaminocarbonyl, pyridin-4-ylmethylamino-carbonyl,    pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,    morpholin4-ylcarbonyl, piperazin-1-ylcarbonyl or    thiazolidin-1-ylcarbonyl wherein any rings comprising R³ are    optionally substituted with one or two groups independently selected    from hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl, or    —CONR^(a)R^(b) where R^(a) and R^(b) are independently hydrogen or    alkyl. Particularly, R³ is 4-hydroxypiperidin-1-ylcarbonyl,    piperidin-1-ylcarbonyl, 2-methoxycarbonylpyrrolidin-1-ylcarbonyl,    4-methylpiperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl,    morpholin4-ylcarbonyl, (2R) or    (2S)-aminocarbonylpyrrolidin-1-ylcarbonyl, (2R) or    (2S)-carboxypyrrolidin-1-ylcarbonyl, (2R) or (2S)-methoxycarbonyl,    pyrrolidin-1-ylcarbonyl, dimethylaminocarbonyl,    3RS-aminocarbonylpiperidin-1-ylcarbonyl,    2S-methoxycarbonyl4R-hydroxypyrrolidin-1-ylcarbonyl, (2R) or    (2S)-dimethylaminocarbonylpyrrolidin-1-ylcarbonyl,    2-(S)-hydroxymethylpyrrolidin-1-ylcarbonyl,    3R-hydroxypyrrolidin-1-ylcarbonyl,    2S-methoxycarbonyl-4S-hydroxypyrrolidin-1-ylcarbonyl,    2S-carboxy-4R-hydroxypyrrolidin-1-ylcarbonyl,    2S-aminocarbonyl-4R-hydroxypyrrolidin-1-ylcarbonyl,    2S-carboxy-4S-hydroxypyrrolidin-1-ylcarbonyl,    2R-methoxycarbonyl-4R-hydroxypyrrolidin-1-ylcarbonyl or    2R-carboxy-4R-hydroxypyrrolidin-1-ylcarbonyl.-   (e) Within the above group Ia, yet another more preferred group of    compounds is that wherein R³ is -(alkylene)-CONR⁹R¹⁰ (where R⁹ is    hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl and R¹⁰ is hydrogen,    alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, or heterocycloalkylalkyl, or R⁹ and R¹⁰    together with the nitrogen atom to which they are attached form    heterocycloalkylamino), wherein any rings comprising R³ are    optionally substituted with one or two groups independently selected    from hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl, or    —CONR^(a)R^(b) where R^(a) and R^(b) are independently hydrogen or    alkyl.-   (f) Within the above group Ia, yet another more preferred group of    compounds is that wherein R³ is haloalkyl or haloalkoxy, preferably    trifluoromethyl or trifluoromethoxy.-   (g) Within the above group Ia, yet another more preferred group of    compounds is that wherein R³ is alkyl or alkoxy, preferably methyl    or methoxy.-   (h) Within the above group Ia, yet another more preferred group of    compounds is that wherein R³ is tetrazol-5-y or tetrazol-5-ylmethyl.-   (i) Within the above group Ia, another more preferred group of    compounds is that wherein R³ is aminosulfonyl or    dimethylaminosulfonyl, preferably aminosulfonyl.-   (j) Within the above group la, another more preferred group of    compounds is that wherein R³ is halo, —CONR⁷R⁸ (where R⁷ is hydrogen    or alkyl and R⁸ is aminocarbonylalkyl or hetereocycloalkylalkyl or    R⁷ and R⁸ together with the nitrogen atom to which they are attached    form heterocycloalkylamino) or -(alkylene)-CONR⁹R¹⁰ (where R⁹ is    hydrogen or alkyl and R¹⁰ is sulfoalkyl, carboxyaminoalkyl,    ammonioalkyl, or heterocycloalkylalkyl, or R⁹ and R¹⁰ together with    the nitrogen atom to which they are attached form    heterocycloalkylamino), wherein any rings comprising R³ are    optionally substituted with one or two groups independently selected    from hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl or    —CONR^(a)R^(b) where R^(a) and R^(b) are independently hydrogen or    alkyl. Preferably R³is fluoro,    2-morpholin-4-ylethylaminocarbonylmethyl,    2-sulfoethylaminocarbonylmethyl,    5-amino-5-carboxypentylaminocarbonylmethyl,    4-methylpiperazin-1-ylcarbonylmethyl,    2-ammonioethylaminocarbonyhnethyl, aminocarbonyl.-   k) Within the above group Ia, another preferred group of compounds    is that wherein R³ is —CONR⁷R⁸, —CH₂CONR⁹R¹⁰ or —C(CH₃)₂CONR⁹R¹⁰    wherein R⁷ and R⁸ or R⁹ and R¹⁰ both are hydrogen, carboxymethyl,    2-hydroxyethyl or 2-phosphonoethyl or R⁷ or R⁹ is hydrogen or methyl    and R⁸ or R¹⁰, respectively, is aminocarbonylmethyl,    1,2-aminocarbonylethyl, 2-aminocarbonyl-1-carboxyethyl, preferably    2S-aminocarbonyl-1-carboxyethyl, 5-amino-5-carboxypentyl, preferably    5S-amino-5-carboxypentyl, 2-arboxyethyl, carboxymethyl,    2-carboxy-3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl,    dimethylaminomethyl, 3-dimethylaminopropyl,    2-hydroxy-1,1-bis-hydroxymethyl-ethyl,    2-hydroxy-1-hydroxymethylethyl, 1,2-dicarboxyethyl, preferably    1R,2-dcarboxyethyl, methyl, 2-[2-(2-methylaminoethoxy)ethoxylethyl,    2-(4-methylpiperazin-1-yl)ethyl, 2-morpholin-4-ylethyl,    2,3,4,5,6-pentahydroxy-hexyl, preferably    2R,3R,4R,5S,6-pentahydroxy-hexyl, 2-piperazin-1-ylethyl,    2-sulfoethyl, 3,4,5,6-tetrahydroxytetrahydro-pyran-2-ylmethyl,    preferably 3S,4S,5R,6S-tetrahydroxy-tetrahydro-pyran-2R-ylmethyl,    2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl, preferably    2,4R,5S-trihydroxy-6R-hydroxymethyl-tetrahydro-pyran-3-yl,    2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoylmethyl,    preferably    2,4R,5S-trihydroxy-6R-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoylmethyl,    trimethylammonioethyl or 2-phosphonoethyl or R⁷ and R⁸ or R⁹ and R¹⁰    together with the nitrogen atom to which they are attached form    2-aminocarbonylpyrrolidin-1-yl, preferably    2R-aminocarbonylpyrrolidin-1-yl, 2-carboxy-4-hydroxypyrrolidin-1-yl,    preferably 2S-carboxy-4-hydroxypyrrolidin-1-yl, or    4-methylpiperazin-1-yl.

Within the above preferred and more preferred groups (a-j), aparticularly preferred group of compounds is that wherein:

R^(z) is halo, hydroxyalkyl, alkylsulfonylamino,alkylsulfonylaminoalkyl, aminosulfonyl, heterocycloalkylcarbonylalkyl,oxoheterocycloalkyl, carboxyalkyl, oxoheterocycloalkylalkyl,heteroaralkyl, ureido, alkylureido, dialkylureido, ureidoalkyl,alkylureidoalkyl, dialkylureidoallyl, thioureido, thioureidoalkyl,—COR¹² (where R¹² is alkyl, hydroxyalkyl, or haloalkyl),-(alkylene)-COR¹² (where R¹² is alkyl or haloalkyl), —CONR¹⁴R¹⁵ (whereR¹⁴ is hydrogen or alkyl and R¹⁵ is hydrogen, alkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl), -(alkylene)-CONR¹⁶R¹⁷ (where R¹⁶ ishydrogen or alkyl and R¹⁷ is hydrogen, alkyl, hydroxyalkyl, aryl,aralkyl, heteroaryl, or heteroaralkyl), —NR¹⁸R¹⁹ (where R¹⁸ is hydrogenor alkyl and R¹⁹ is hydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, orheteroaralkyl), -(alkylene)-NR²⁰R²¹ (where R²⁰ is hydrogen or alkyl andR²¹ is hydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, orheteroaralkyl), —NR²⁶SO₂NR²⁷R²⁸ (where R²⁶ and R²⁷ are independentlyhydrogen or alkyl, and R²⁸ is hydrogen, alkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl or R²⁷ and R²⁸ together with the nitrogenatom to which they are attached form heterocycloamino), or-alkylene)-NR²⁹SO₂NR³⁰R³¹ (where R²⁹ and R³⁰ are independently hydrogenor alkyl, and R³¹ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl or R³⁰ and R³¹ together with the nitrogen atom to whichthey are attached from heterocycloamino).

Preferably, R^(z) is aminosulfonyl, alkylsulfonylaminoalkyl, halo,carboxyalkyl, hydroxyalkyl, heterocycloalkylcarbonylalkyl, ureidoalkyl,alkylureidoalkyl, dialkylureidoalkyl, —CONR¹⁴R¹⁵ (where R¹⁴ is hydrogenor alkyl and R¹⁵ is hydrogen or alkyl), -(alkylene)-CONR¹⁶R¹⁷ (where R¹⁶is hydrogen or alkyl and R¹⁷ is hydrogen, alkyl, or hydroxyalkyl), or-(alkylene)-NR²⁰R²¹ (where R²⁰ is hydrogen or alkyl and R²¹ is hydrogen,alkyl, hydroxyalkyl or acyl).

Preferably, R^(z) is fluoro, aminosulfonyl, ureidomethyl,methylaminocarbonylmethyl, 2-tert-butylureidomethyl,3,3-dimethylureidomethyl, aminomethyl, piperazin-1-ylcarbonylmethyl,carboxymethyl, hydroxymethylcarbonylaminomethyl, aminocarbonyl,acetylaminomethyl, aminocarbonylmethyl, methylaminocarbonylmethyl,dimethylaminocarbonylmethyl, 2-hydroxyethylaminocarbonylmethyl,morpholin-4-ylcarbonylmethyl, methoxycarbonylaminomethyl, hydroxymethyl,or methylsulfonylaminomethyl.

Within the above preferred, more preferred, and even more preferredgroups, a particularly preferred group of compounds is that wherein:

R¹³ is hydrogen, hydroxy, methoxy, or ethoxycarbonyl, more preferablyhydrogen.(II). Another Preferred Group of Compounds is Represented by the FormulaIb:

wherein:

R³ is hydrogen, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyanoalkyl,tetrazol-5-yl, tetraol-5-ylalkyl, hydroxyalkylcarbonyl, aminosulfonyl,alkylaminosulfonyl, dialkylarninosulfonyl, —NHSO₂R (where R is alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl or heterocycloalkylalkyl), —SO₂NHCOR⁶ (where R⁶ isalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, orheterocycloalkylalkyl), —CONR⁷R⁵ or —COCONR⁷R⁸ (where R⁷ is hydrogen,alkyl, hydroxyalkyl, alkoxyalkyl and R⁸ is hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or hetereocycloalkylalkyl or R⁷ and R⁸ together with thenitrogen atom to which they are attached form heterocycloalkylamino),-(alkylene)-CONR⁹R¹⁰ (where R⁹ is hydrogen, alkyl, hydroxyalkyl,alkoxyalkyl and R¹⁰ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocycloalkylalkyl, or R⁹ and R¹⁰ together with the nitrogen atom towhich they are attached form heterocycloalkylamino), —CONHSO₂R¹¹ (whereR¹¹ is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclalkyl,or heterocycloalkylalkyl), or -(alkylene)-CONHSO₂R¹¹ (where R¹¹ isalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, orheterocycloalkylalkyl), wherein any rings comprising R³ are optionallysubstituted with one or two groups independently selected from hydroxy,hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl or —CONR^(a)R^(b) whereR^(a) and R^(b) are independently hydrogen or alkyl;

R^(x) is hydrogen or halo; and

R^(z) is —SO₂NR²²R²³ (where R²² is hydrogen or alkyl and R²³ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R²² andR²³ together with the nitrogen atom to which they are attached fromheterocycloamino) or -(alkylene)-SO₂NR²⁴R²⁵ (where R²⁴ is hydrogen oralkyl and R²⁵ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl or R²⁴ and R²⁵ together with the nitrogen atom to whichthey are attached from heterocycloamino); and

R¹³ is hydrogen, hydroxy, (C₁₋₁₀)alkoxy, —C(O)R³⁵ where R³⁵ is alkyl,aryl, haloalkyl, or cyanoalkyl, or —C(O)OR³⁶ where R³⁶ is alkyl,hydroxyalkyl, acyl, or haloalkyl; or a pharmaceutically acceptable saltthereof.

-   (a) Within the above group Ia, a more preferred group of compounds    is that wherein R³ is hydrogen.-   (b) Within the above group Ia, another more preferred group of    compounds is that wherein R³ is halo, preferably chloro or fluoro,    more preferably fluoro.-   (c) Within the above group Ia, another more preferred group of    compounds is that wherein R³ is —SO₂NHCOR⁶ where R⁶ is as defined in    its broadest terms in the Summary of the Invention. Preferably R⁶ is    alkyl, aralkyl, aryl, heteroaralkyl or heterocycloalkylalkyl. More    preferably R³ is aminosulfonyl, —SO₂NHCOCH₃,    2-phenyethylcarbonyl-aminosulfonyl, phenylcarbonylaminosulfonyl,    3-phenylpropylcarbonylaminosulfonyl, benzylcarbonylaminosulfonyl,    2-(3,4-dichlorophenyl)ethylcarbonylaminosulfonyl,    2-pyridin-3-ylethylcarbonylaminosulfonyl,    2-piperidin-3-ylethylcarbonylaminosulfonyl. Even more preferably R³    is —SO₂NHCOCH₃.-   (d) Within the above group Ia, yet another more preferred group of    compounds is that wherein R³ is —CONR⁷R⁵ (where R⁷ is hydrogen,    alkyl, hydroxyalkyl, or alkoxyalkyl and R⁸ is hydrogen, alkyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, aralkyl, heteroaryl,    heteroaralkyl, or hetereocycloalkylalkyl or R⁷ and R⁸ together with    the nitrogen atom to which they are attached form    heterocycloalkylamino, wherein any rings comprising R³ are    optionally substituted with one or two groups independently selected    from hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl or    —CONR^(a)R^(b) where R^(a) and R^(b) are independently hydrogen or    alkyl). Preferably R⁷ is hydrogen or alkyl, and R⁸ is hydrogen,    alkyl, aralkyl, or heteroaralkyl, or R⁷ and R⁸ together with the    nitrogen atom to which they are attached form heterocycloalkylamino.    More preferably, R⁷ and R⁸ together with the nitrogen atom to which    they are attached form heterocycloalkylamino, optionally substituted    with one or two groups independently selected from hydroxy,    hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl or —CONR^(a)R^(b) where    R^(a) and R^(b) are independently hydrogen or alkyl. Even more    preferably, R³ is aminocarbonyl, dimethylaminocarbonyl,    2-morpholin-4-ylethylaminocarbonyl, 2-phenethylaminocarbonyl,    methylaminocarbonyl, pyridin-2-ylmethylaminocarbonyl,    furan-2-ylmethylaminocarbonyl, 2-pyridin-4-ylethylaminocarbonyl,    2-pyridin-3-ylethylaminocaxbonyl, 2-pyridin-2-ylethylaminocarbonyl,    pyridin-4-ylmethylamino-carbonyl, pyrrolidin-1-ylcarbonyl,    piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,    piperazin-1-ylcarbonyl or thiazolidin-1-ylcarbonyl, wherein any    rings comprising R³ are optionally substituted with one or two    groups independently selected from hydroxy, hydroxyalkyl, carboxy,    alkoxycarbonyl, alkyl or —CONR^(a)R^(b) where R^(a) and R^(b) are    independently hydrogen or alkyl. Particularly, R³ is    4-hydroxypiperidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,    2-methoxycarbonylpyrrolidin-1-ylcarbonyl,    4-methylpiperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl,    morpholin-4-ylcarbonyl, (2R) or    (2S)-aminocarbonylpyrrolidin-1-ylcarbonyl, (2R) or    (2S)-carboxypyrrolidin-1-ylcarbonyl, (2R) or (2S)-methoxycarbonyl,    pyrrolidin-1-ylcarbonyl, dimethylaminocarbonyl,    3RS-aminocarbonylpiperidin-1-ylcarbonyl,    2S-methoxycarbonyl-4R-hydroxypyrrolidin-1-ylcarbonyl, (2R) or    (2S)-dimethylaminocarbonylpyrrolidin-1-ylcarbonyl,    2-(S)-hydroxymethylpyrrolidin-1-ylcarbonyl,    3R-hydroxypyrrolidin-1-ylcarbonyl,    2S-methoxycarbonyl-4S-hydroxypyrrolidin-1-ylcarbonyl,    2S-carboxy-4R-hydroxypyrrolidin-1-ylcarbonyl,    2S-aminocarbonyl-4R-hydroxypyrrolidin-1-ylcarbonyl,    2S-carboxy-4S-hydroxypyrrolidin-1-ylcarbonyl,    2R-methoxycarbonyl-4R-hydroxypyrrolidin-1-ylcarbonyl or    2R-carboxy-4R-hydroxypyrrolidin-1-ylcarbonyl.-   (e) Within the above group Ia, yet another more preferred group of    compounds is that wherein R³ is -(alkylene)-CONR⁹R¹⁰ (where R⁹ is    hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl and R¹⁰ is hydrogen,    alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, or heterocycloalkylalkyl, or R⁹ and R¹⁰    together with the nitrogen atom to which they are attached form    heterocycloalkylamino), wherein any rings comprising R³ are    optionally substituted with one or two groups independently selected    from hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl or    —CONR^(a)R^(b) where R^(a) and R^(b) are independently hydrogen or    alkyl.-   (f) Within the above group Ia, yet another more preferred group of    compounds is that wherein R³ is haloalkyl or haloalkoxy, preferably    trifluoromethyl or trifluoromethoxy.-   (g) Within the above group Ia, yet another more preferred group of    compounds is that wherein R³ is alkyl or alkoxy, preferably methyl    or methoxy.-   (h) Within the above group Ia, yet another more preferred group of    compounds is that wherein R³ is tetrazol-5-y or tetrazol-5-ylmethyl.-   (i) Within the above group Ia, another more preferred group of    compounds is that wherein R³ is aminosulfonyl or    dimethylaminosulfonyl, preferably aminosulfonyl.

Within the above preferred and more preferred groups (a-i), aparticularly preferred group of compounds is that wherein:

R^(x) is fluoro, chloro, or hydrogen, preferably hydrogen; and

R^(z) is aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl,aminosulfonyhnethyl, methylaminosulfonylmethyl, ordimethylaminosulfonylmethyl.

Within the above preferred, more preferred, and even more preferredgroups, a particularly preferred group of compounds is that wherein:

R¹³ is hydrogen, hydroxy, methoxy, or ethoxycarbonyl, preferablyhydrogen.(III) Yet Another Preferred Group of Compounds of Formula I are Thosewherein the Moiety:

is 3′-acetylphenyl, 3′-hydroxyphenyl, 2′-hydroxyphenyl,3′-aminocarbonylphenyl, 3′-cyanophenyl, 5′-fluoro-2′-hydroxyphenyl,5′-chloro-2′-hydroxyphenyl, 2′-hydroxy-methylphenyl, 2′-hydroxyphenyl,5′-carboxy-2′-hydroxyphenyl, 2′,5′-dihydroxyphenyl,5′-cyano-2′-methoxyphenyl, 5′-aminocarbonyl-2′-methoxyphenyl,2′,6′-dihydroxyphenyl, 2′-hydroxy-5′-nitrophenyl, 2′-cyanophenyl,3′-hydroxymethylphenyl, 5′-cyano-2′-hydroxyphenyl,5′-aminocarbonyl-2′-hydroxyphenyl, 2′,6′-dihydroxyphenyl,5′-aminomethyl-2′-hydroxyphenyl, 2′-hydroxy-5′-ureidomethylphenyl,2′-hydroxy-5′-imidazol-2-ylphenyl, 5′-amino-2′-hydroxyphenyl,2′-hydroxy-5′-ureidophenyl,2′-hydroxy-5′-(2-morpholin-4-ylethyl)aminocarbonyl-phenyl,3′-bromo-2′-hydroxy-5′-hydroxymethylphenyl,5′-(2-cyanoethyl)-2′-hydroxyphenyl,3′-bromo-5′-carboxymethyl-2′-hydroxyphenyl,5′-(2-carboxyethyl)-2′-hydroxyphenyl,5′-aminocarbonylmethyl-2′-hydroxyphenyl,3′,5′-dichloro-2′-hydroxyphenyl,2′-hydroxy-5′-[2-(2-hydroxyethoxy)ethylaminocarbonyl]phenyl,5′-dimethylaminosulfonylamino-2′-hydroxy-phenyl,3′-bromo-5′-chloro-2′-hydroxyphenyl,2′-hydroxy-5′-(4-methylpiperazin-1-ylcarbonyl)phenyl,2′-hydroxy-5′-(4-methylpiperazin-1-ylemthyl)phenyl,5′-carbamimidoyl-2′-hydroxyphenyl,5′-(2-dimethylaminoethylaminocarbonyl)-2′-hydroxyphenyl, or5′-aminocarbonyl-2′-hydroxyphenyl. Preferably 2′-hydroxyphenyl,5′-fluoro-2′-hydroxyphenyl, 5′-chloro-2′-hydroxyphenyl,2′-hydroxymethylphenyl, 2′-hydroxyphenyl, 5′-carboxy-2′-hydroxyphenyl,2′,5′-dihydroxyphenyl, 2′,6′-dihydroxyphenyl, 2′-hydroxy-5′-nitrophenyl,5′-cyano-2′-hydroxyphenyl, 5′-aminocarbonyl-2′-hydroxyphenyl,2′,6′-dihydroxyphenyl, 5′-aminomethyl-2′-hydroxyphenyl,2′-hydroxy-5′-ureidomethylphenyl, 2′-hydroxy-5′-imidazol-2-ylphenyl,5′-amino-2′-hydroxyphenyl, 2′-hydroxy-5′-ureidophenyl,2′-hydroxy-5′-(2-morpholin-4-ylethyl)aminocarbonyl-phenyl,3′-bromo-2′-hydroxy-5′-hydroxymethylphenyl, 5′-(2-cyanoethyl)-2′-hydroxyphenyl, 3′-bromo-5′-carboxymethyl-2′-hydroxyphenyl,5′-(2-carboxyethyl)-2′-hydroxyphenyl,5′-aminocarbonylmethyl-2′-hydroxyphenyl,3′,5′-dichloro-2′-hydroxyphenyl,2′-hydroxy-5′-[2-(2-hydroxyethoxy)ethylaminocarbonyl]phenyl,5′-dimethylaminosulfonylamino-2′-hydroxy-phenyl,3′-bromo-5′-chloro-2′-hydroxyphenyl,2′-hydroxy-5′-(4-methylpiperazin-1-ylcarbonyl)phenyl,2′-hydroxy-5′-(4-methylpiperazin-1-ylmethyl)phenyl,5′-carbamimidoyl-2′-hydroxyphenyl,5′-methylaminocarbonylmethyl-2′-hydroxyphenyl,5′-(2-dimethylaminoethylaminocarbonyl)-2′-hydroxyphenyl, or5′-aminocarbonyl-2′-hydroxyphenyl. More preferably,2′,6′-dihydroxyphenyl, 5′-fluoro-2′-hydroxyphenyl,3′-aminosulfonylphenyl, 5′-aminocarbonyl-2′-hydroxyphenyl,5′-aminocarbonylmethyl-2′-hydroxyphenyl,5′-methylaminocarbonylmethyl-2′-hydroxyphenyl,5′-hydroxymethyl-2′-hydroxyphenyl,5′-acetylaminomethyl-2′-hydroxyphenyl, 2′-hydroxy-5′-ureidophenyl;2′-hydroxy-5′-ureidomethylphenyl,2′-hydroxy-5′-N-methylureidomethyl-phenyl,2′-hydroxy-5′-N,N-dimnethylureidomethylphenyl, or5′-methylsulfonylamino-2′-hydroxyphenyl.

Within this group, a more preferred group of compounds is that wherein Rand R² are hydrogen, X¹ is nitrogen, X²—X⁴ are carbon and R³ ishydrogen, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy,methoxy, aminocarbonyl, dimethylaminocarbonyl, tetrazol-5-yl,tetrazol-5-ylmethyl cyanomethyl, acetylaminosulfonyl, or aminosulfonyl.

(IV) Yet Another Preferred Group of Compounds of Formula I are Thosewherein the Moiety:

is a group of the formula:

where R^(z) is fluoro, aminosulfonyl, ureidomethyl, —CH₂NHCONCH₃,—CH₂NHCON-tert-butyl, N,N-dimethylureidomethyl, aminomethyl,piperazin-1-ylcarbonylmethyl, carboxymethyl, —CH₂NHCOCH₂OH,aminocarbonyl, acetylaminomethyl, aminocarbonylmethyl,methylaminocarbonyhnethyl, dimethylaminocarbonylmethyl,2-hydroxyethylaminocarbonylmethyl, morpholin-4-ylcarbonylmethyl,methoxycarbonylaminomethyl, hydroxymethyl, or methylsulfonylaminomethyl.

Reference to the preferred embodiments set forth above is meant toinclude all combinations of particular and preferred groups unlessstated otherwise.

(V) Another Preferred Group of Compounds of Formula I are the Following:

2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-succinamic(Compound 121);

({2-[5-(5-carbaminidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-carboxymethyl-amino)-aceticacid (Compound 122);

2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-succinicacid (Compound 123);

1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-pyrrolidine-2-carboxamide(Compound 124);

1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-4-hydroxy-pyrrolidine-2-carboxylicacid (Compound 125);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetamide(Compound 126);

2-[5-(5-arbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N,N-diethyl-acetamide(Compound 127);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-acetamide(Compound 128);

{2-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-aceticacid (Compound 129);

2-[5-(5-arbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-carbamoylmethyl-acetamide(Compound 130);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2dimethylamino-ethyl)-acetamide (Compound 131);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(3-dimethylamino-propyl)-acetamide(Compound 132);

3-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-propionicacid (Compound 133);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-N-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-acetamide(Compound 134);

2-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(S,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-acetamide(Compound 135);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-acetamide(Compound 136);

2-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)-acetamide(Compound 137);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-acetamide(Compound 138);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-acetamide(Compound 139);

2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-succinamide(Compound 140);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-[(2,4,5-trihydoxy-6-hydoxymethyl-tetrahydo-pyran-3-ylcarbamoyl)-methyl]-acetamide(Compound 141);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-{3-[2-2-ethoxy-ethoxy)-ethoxy]-propyl}-acetamide(Compound 142);

(2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydtoxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-ethyl)-phosphonicacid (Compound 143);

{2-[{2-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-(2-phosphono-ethyl)-amino]-ethyl}-phosphonicacid (Compound 144);

2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinamicacid (Compound 145);

({2-[5-(5-carbaminidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionyl}-carboxymethyl-amino)-aceticacid (Compound 146);

2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinicacid (Compound 147);

1-{2-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionyl}-pyrrolidine-2-carboxamide(Compound 148);

1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionyl}-4-hydroxy-pyrrolidine-2-carboxylicacid (Compound 149);

2-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-isobutyramide(Compound 150);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dinydroxy-5′-sulfamoyl-biphenyl-3-yl]-N,N-dimethyl-isobutyramide(Compound 151);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-isobutyramide(Compound 152);

{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-aceticacid (Compound 153);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-carbamoylmethyl-isobutyramide(Compound 154);

2-[5-(5-carbamimidoyl-1H-benzohnidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-dimethylamino-ethyl)-isobutyramide(Compound 155);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(3-dimethylamino-propyl)-isobutyramide(Compound 156);

3-{2-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-propionicacid (Compound 157);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-yl]-N-methyl-N-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-isobutyramide(Compound 158);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-isobutyramide(Compound 159);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)-isobutyramide(Compound 161);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-isobutyramide(Compound 162);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-isobutyramide(Compound 163);

2S-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinamide(Compound 164);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-[(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-methyl]-isobutyramide(Compound 165);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-isobutyramide(Compound 166);

(2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-ethyl)-phosphonicacid (Compound 167);

{2-[{2-[5-(5-carbaminidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionyl}-2-phosphono-ethyl)-amino]-ethyl}-phosphonicacid (Compound 168);

2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinamicacid (Compound 169);

({2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionyl}-carboxymethyl-amino)-aceticacid (Compound 170);

2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinicacid (Compound 171);

1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionyl}-pyrrolidine-2-carboxamide(Compound 172);

1-{2-[5-(5-carbamimidoyl-1H-benzimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethylbiphenyl-3-yl]-2-methyl-propionyl}-4-hydroxy-pyrrolidine-2-carboxylicacid (Compound 173);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-isobutyramide(Compound 174);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N,N-dimethyl-isobutyramide(Compound 175);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-isobutyramide(Compound 176);

{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-aceticacid (Compound 177);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-carbamoylmethyl-isobutyramide(Compound 178);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(2-dimethylamino-ethyl)-isobutyramide(Compound 179);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(3-methylamino-propyl)-isobutyramide(Compound 180);

3-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-propionicacid (Compound 181);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-isobutmide(Compound 182);

2-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-methyl-N-{2-[2-(2-methylamino-ethoxy)-ethoxy)-thyl}-isobutyramide(Compound 183);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-isobutyramide(Compound 184);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-methyl-N-2,3,4,5,6-pentahydroxy-hexyl)-isobutyramide(Compound 185);

2-[5-(5-carbaminidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-isobutyramide(Compound 186);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-methyl-isobutyramide(Compound 187);

2-{2-[5-(5-carbaminidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinamide(Compound 188);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-[(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-methyl]-isobutyramide(Compound 189);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-isobutyramide(Compound 190);

(2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-ethyl)-phosphonicacid (Compound 191);

{2-[{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionyl}-(2-phosphono-ethyl)-amino]-ethyl}-phosphonicacid (Compound 192);

2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-succinamicacid (Compound 193);

{[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-carboxymethyl-amino}-aceticacid (Compound 194);

2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-succinicacid (Compound 195);

1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-pyrrolidine-2-carboxylicacid (Compound 196);

1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-4-hydroxy-pyrrolidine-2-carboxylicacid (Compound 197);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 198);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-N,N-dimethyl-3-carboxamide(Compound 199);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-(2-hydroxy-1-hydroxymethyl-ethyl)-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 200);

{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-aceticacid (Compound 201);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-N-carbamoylmethyl-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 202);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-(2dimethylamino-ethyl)-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 203);

3-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-propionicacid (Compound 204);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-methyl-N-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 205);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-(3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 206);

5-(5-carbamimidoyl-1H-benzoimidazol1-2-yl)-6,2′-dihydroxy-N-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 207);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-methyl-N-2,3,4,5,6-pentahydroxy-hexyl)-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 209);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 210);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-methyl-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 211);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-[(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-methyl]-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 213);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 214);

(2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-ethyl)-phosphonicacid (Compound 214);

{2-[[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-(2-phosphono-ethyl)-amino]-ethyl}-phosphonicacid (Compound 215);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N,N-bis-(2-hydroxy-ethyl)-5′-methyl-biphenyl-3-carboxyamide(Compound 217);

(2-{[5(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-ethyl)-trimethyl-ammonium(Compound 218);

2-{5-[4-(2-amino-ethyl)-piperazine-1-carbonyl]-2,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl}-1H-benzoimidazole-5-carboxamidine(Compound 219);

2-amino-6-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-hexanoicacid (Compound 220);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-hydroxy-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 221);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N,N-dimethyl-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 222);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 223);

1-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-pyrrolidine-2-carboxamide(Compound 224);

2-[2,2′-dihydroxy-5-(morpholine-4-carbonyl)-5′-sulfamoyl-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(Compound 225);

1-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-pyrrolidine-2-carboxylicacid (Compound 226);

[(2-{4-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-piperazin-1-yl}-ethylamino)-dimethylamino-methylene]-dimethyl-ammonium(Compound 228);

2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-ethanesulfonicacid (Compound 234);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide(Compound 235);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetamide(Compound 238);

2-amino-6-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-hexanoicacid (Compound 112);

2-{2,2′-dihydroxy-5-[2-(4methyl-piperazin-1-yl)-2-oxo-ethyl]-5′-sulfamoyl-biphenyl-3-yl}-1H-benzoimidazole-5-carboxamidine(Compound 113);

(2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-ethyl)-trimethyl-ammonium(Compound 105);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-carbamoylmethyl-methyl-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 106);

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-(2-piperazin-1-yl-ethyl)-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 107); and

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-methyl-5′-sulfamoyl-biphenyl-3-carboxamide(Compound 229).

General Synthetic Scheme

Compounds of this invention can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition) and Larock's ComprehensiveOrganic Transformations (VCH Publishers Inc., 1989). These schemes aremerely illustrative of some methods by which the compounds of thisinvention can be synthesized, and various modifications to these schemescan be made and will be suggested to one skilled in the art havingreferred to this disclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., more preferably from about 0° C. to about 125° C.and most preferably at about room (or ambient) temperature, e.g., about20° C.

Compounds of Formula I in which X¹ is —N—, R¹³ is hydrogen, R³ ishydrogen, halo, alkyl, haloalkyl, cyanoalkyl, tetrazol-5-yl,tetrazol-5-ylalkyl, aminosulfonyl, —SO₂NHCOR⁶, —CONHSO₂R¹¹ or-(alkylene)-CONHSO₂R¹¹ where R⁶ and R¹¹ are as described in the Summaryof the Invention and X², X³, X⁴, R¹, R², R^(x), R^(y), and R^(z) are asdefined in the Summary of the Invention can be prepared as described inScheme I below.

A compound of formula 4 where R¹ and R² are as defined in the Summary ofthe Invention and R³ is hydrogen, halo, alkyl, haloalkyl, cyanoalkyl,tetrazol-5-yl, tetrazol-5-ylalkyl, aminosulfonyl, —SO₂NHCOR⁶,—CONHSO₂R¹¹ or -(alkylene)-CONHSO₂R¹¹ where R⁶ and R¹¹ are as describedin the Summary of the Invention and X is halo, preferably bromo or iodocan be prepared as disclosed in method (a) above, by halogenating acompound of formula 1 (where R is hydrogen or hydroxy protecting group)with a suitable halogenating agent such as N-bromosuccinimide,N-iodosuccinimide, and the like. The reaction is carried out in asuitable organic solvent such as dimethylformamide.

Alternately, a compound of formula 4 can be prepared as disclosed inmethod (b) above, by formulating of a phenol derivative of formula 2(where R¹ and R² are as defined in the Summary of the Invention and R³is hydrogen, halo, alkyl, haloalkyl, cyanoalkyl, tetrazol-5-yl,tetrazol-5-ylalkyl, or -(alkylene)-CONHSO₂R¹¹ where R⁶ and R¹¹ are asdescribed in the Summary of the Invention) to provide a compound offormula 3 which is then halogenated under the reaction conditionsdescribed in method (a) above. The formulation reaction is carried outin the presence of magnesium chloride and an organic base such astriethylamine, and the like and in a suitable organic solvent such asacetonitrile, and the like.

Compounds of formulae 1 and 2 are either commercially available or theycan be prepared by methods well known in the art. For example, compoundsof formula 1 such as 5-fluoro-2-hydroxybenzaldehyde,5-methyl-2-hydroxybenzaldehyde, and salicyaldehyde are commerciallyavailable. Compounds of formula 2 such as 4-fluorophenol, phenol,p-cresol, and 4-hydroxybenzyl cyanide are commercially available.Compounds of formula 2 where R³ is tetrazolyl or tetrazol-5-ylalkyl canbe prepared from 4-hydroxybenzonitrile and 4-hydroxybenzyl cyaniderespectively, by first protecting the hydroxy group with a suitablehydroxy protecting group and then treating the resulting compound withazidotributyltin in an aromatic organic solvent such as toluene, and thelike. Compounds of formula 4 where R³ is —CONHSO₂R¹¹ or-(alkylene)-CONHSO₂R¹¹ can be readily prepared from3-formyl-4-methoxy-5-bromobenrzoic acid and2-(3-formyl-4-methoxy-5-bromophenyl)acetic acid by first converting theacid to an acid halide such as acid chloride with a suitablehalogenating agent such as oxalyl chloride, and the like. Treatment ofthe acid halide with a sulfonamide of the formula R¹¹SO₂NH₂ where R¹¹ isas defined in the Summary of the Invention then provides the desiredcompound. 3-Formyl-4-methoxy-5-bromobenzoic acid and2-(3-formyl-4-methoxy-5-bromophenyl)acetic acid can be prepared by theprocedures disclosed in Applicants' Patent application Ser. No.10/190,147 the disclosure of which is incorporated herein by referencein its entirety. Compounds of formula 4 where R³ is aminosulfonyl or—SO₂NHCOR⁶ can be prepared as described in working Examples 12-14 below.

Protection of the hydroxy group in 4 (where R is hydrogen) with asuitable hydroxy protecting group such as alkyl, methyoxyethoxymethyl,and the like, provides a compound of formula 5. A comprehensive list ofsuitable hydroxy protective groups can be found in T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981,the disclosure of which is incorporated herein by reference in itsentirety. Preferred hydroxy protecting group is 2-methoxyethoxymethyl.The reaction is typically carried out in the presence of a base such asdiispropylethylamine, and the like and in a halogenated organic solventsuch as dichloromethane, carbon tetrachloride, chloroform, and the like.

Compound 5 is converted into phenyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl) derivative 6 by heating 5with bispinacolato diboron in the presence of potassium acetate in thepresence of Pd(dppf)Cl₂.

Treatment of 6 with a halobenzene of formula Ph(R^(x), R^(y), R^(z))Xwhere X is halo and R^(x), R^(y) and R^(z) are as defined in the Summaryof the Invention provides a biphenyl compound of formula 8. The reactionis carried out in the presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium and in a suitable organic solventsuch as toluene or dimethoxyethane and a base such as aqueous sodiumcarbonate, potassium carbonate and the like. Compounds of formula 7 areeither commercially available or they can be prepared by methods wellknown in the art. For example, 2-bromo-4-fluorophenol is commerciallyavailable. 1-(3-Bromo-4-methoxyethoxymethoxybenzyl)-3-tert-butyl ureacan be prepared by treating 3-bromo-4-hydroxybenzonitrile withmethoxyethoxymethyl chloride in the presence of a base such asdiisopropylamine, and the like, followed by reduction of the resulting3-bromo-4-methylethoxymethoxy)benzonitrile to3-bromo-4-methoxyethoxymethoxybenzylamine with a suitable reducing agentsuch as diborane. Treatment of 3-bromo-4-methylethoxybenzylamine withtert-butylisocyanate then provides the desired compound.1-(3-bromo-4-methoxyethoxymethoxybenzyl)-3-tert-butyl urea can beconverted to 1-(3-bromo-4-methoxyethoxymethoxybenzyl)urea, if desired,by removal of the tert-butyl group under acidic hydrolysis reactionconditions.

Condensation of 8 with a 1,2-diamino compound of formula 9 provides acompound of Formula I where X¹ is —N—. The reaction is carried out inthe presence of a suitable oxidant such as benzoquinone, air oxidation,or FeCl₃ and O₂ and in a suitable organic solvent such as methanol,ethanol, and the like.

Compounds of formula 9 are commercially available or they can beprepared by methods well known in the art. For example, synthesis of3,4-diaminobenzamidine monohydrochloride is known in the art.

Compounds of Formula I in which X¹ is —CH—, R¹³ is hydrogen, and X², X³,X⁴, R¹, R², R^(x), R^(y), and R^(z) are as defined in the Summary of theInvention can be prepared as described in Scheme II below.

Protection of the hydroxy group in a compound of formula 8 with asuitable hydroxy protecting group provides a compound of formula 10. Acomprehensive list of suitable hydroxy protective groups can be found inT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,Inc. 1981, the disclosure of which is incorporated herein by referencein its entirety. Preferred hydroxy protecting group is2-methoxyethoxymethyl. The reaction is typically carried out in thepresence of a base such as diispropylethylamine, and the like and in ahalogenated organic solvent such as dichloromethane, carbontetrachloride, chloroform, and the like.

Ethynylation of 10 utilizing a modified procedure described in Muller,S.; Liepold, B.; Roth G. J.; Bestmann H. J. Synlett 1996, 6, 521-522provides a ethynylbiphenyl compound of formula 11.

Reaction of a compound of formula 11 with a cyano compound of formula 12where PG¹ is a suitable nitrogen protecting group such asmethylsulfonyl, tert-butoxycarbonyl, trifluoroacetyl, and the like, andX is halo, utilizing the reaction conditions described in Sakamoto, T;Kondo, Y.; Iwashita, S.; Nagano, T.; Yamanaka, H. Chem. Pharm. Bull.1988, 36, 1305 provides 5-cyano-2-biphenyl-3-ylindole compound offormula 13 (where X¹, X², X³ and X⁴ are carbon and PG¹ is not hydrogen).Deprotection of the amino group in 13 provides a5-cyano-2-biphenyl-3-yl-1H-indole compound of formula 14. The reactionconditions utilized in the deprotection step depends on the nature ofthe nitrogen protecting group. For example, if the protecting group ismethylsulfonyl it is removed under basic hydrolysis reaction conditions.Suitable bases are aqueous sodium hydroxide, potassium hydroxide, andthe like. The reaction is carried out in an alcoholic solution such asmethanol, ethanol, and the like. If the protecting group istert-butoxycarbonyl it is removed under acidic hydrolysis reactionconditions. Compounds of formula 12 are either commercially available orthey can be prepared by methods well known in the art.

The hydroxy-protecting group in 14 is then removed to provide5-cyano-2-(2-hydroxybiphenyl-3-yl)-1H-indole 15. The reaction conditionsemployed for the deprotection reaction depend on the nature of thehydroxy protecting group. For example, if the protecting group is2-methoxyethoxymethyl, it is removed by treating 15 with an acid undernon-aqueous reaction conditions, in a suitable alcoholic solvent.

The cyano group in compound 15 is then converted into the carbamimidoylgroup by first treating 15 with hydrogen chloride gas in an anhydrousalcoholic solvent such as methanol, ethanol and the like, and thentreating the resulting(5-methoxycarbonimidolyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole 16 withan inorganic base such as ammonium carbonate, and the like in analcoholic solvent such as methanol, ethanol, or with excess ammonia togive resulting (5-carbamimidolyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indoleof Formula I. Alternatively, compound 15 can be converted to a compoundof Formula I by first refluxing it with hydroxylamine in an alcoholicsolvent such as ethanol and then treating the resulting(N-hydroxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole withacetic anhydride in acetic acid to give(N-acetoxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole. Theacetoxy group is then removed under hydrogenation reaction conditions bytreating N-acetoxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indolewith 10% palladium in an alcoholic solvent such as methanol, ethanol,and the like.

Compounds of Formula I in which X¹ is —N—, R¹³ is hydrogen, R³ is—CONR⁷R⁸ or -alkylene)-CONR⁹R¹⁰ where R⁷, R⁸, R⁹ and R¹⁰ are asdescribed in the Summary of the Invention and X², X³, X⁴, R¹, R², R^(x),R^(y), R^(z) and R¹¹ are as defined in the Summary of the Invention canbe prepared as described in Scheme III below.

Compounds of Formula I in which X¹ is —N—, R¹³ is hydrogen, R³ is—CONR⁷R⁸ or -(alkylene)-CONR⁹R¹⁰ where R⁷, R⁸, R⁹ and R¹⁰ are asdescribed in the Summary of the Invention and X², X³, X⁴, R¹, R², R^(x),R^(y), R^(z) and R¹¹ are as defined in the Summary of the Invention canbe prepared by first converting a compound of formula 18 (where R ishydroxy protecting group and R³ is a —COOR′ or -alkylene-COOR′ groupwhere R′ is alkyl) to a compound of formula 19 (where R³ is an —COOR′ or-alkylene-COOR′ group where R′ is alkyl) as described in Scheme I.Compounds of formula 18 are either commercially available or they can beprepared by methods well known in the art. Some such methods aredescribed in Applicant's PCT Application Publication No. WO 00/35886 thedisclosure of which is incorporated herein by reference in its entirety

Hydrolysis of the ester group provides a corresponding compound offormula 20 (where R³ is an —COOH or -alkylene-COOH). Amination of 20with an amine of formula NHR⁷R⁵ or NHR⁹R then provides a compound ofFormula I. The amination reaction is carried out reacting 20 with theamine in the presence of a suitable coupling agent e.g.,benzotriazole-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate(PyBOP®), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HBTU),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), 1-(3-imethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC), or 1,3-dicyclohexylcarbodiimide (DCC), optionallyin the presence of 1-hydroxybenzotriazole (HOBT), and a base such asN,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and thelike. The reaction is typically carried out at 20 to 30° C., preferablyat about 25° C., and requires 2 to 24 h to complete. Suitable reactionsolvents are inert organic solvents such as dimethylformamide, and thelike.

Compounds of Formula I can be converted to other compounds of Formula I.For example, a compound of Formula I where R^(x) is alkoxy, can beconverted to corresponding compound of Formula I where R^(x) is hydroxyby hydrolysis of the alkoxy group by a suitable dealkylating reagentsuch as hydrobromic acid, and the like. A compound of Formula I whereR^(z) is cyano can be converted to a corresponding compound of Formula Iwhere R^(z) is aminocarbonyl under hydrolysis reaction conditions. Thecyano group can also be reduced to give aminomethyl group which can betreated with isocyanate or thiocyanate to give corresponding compound ofFormula I where R^(z) is ureidomethyl or thioureidomethyl respectively.A compound of Formula I where R¹³ is hydrogen can be converted to acorresponding compound of Formula I where R¹³ is hydroxy or alkoxy byreacting it with hydroxylamine or alkoxyamine under conditions wellknown in the art.

Utility

The compounds of this invention inhibit Factors VIIa, IXa, Xa, and XIa,in particular Factor VIIa, and are therefore useful as anticoagulantsfor the treatment or prevention of thromboembolic disorders in mammals.

Particular disease states which may be mentioned include the therapeuticand/or prophylactic treatment of venous thrombosis (e.g. DVT) andpulmonary embolism, arterial thrombosis (e.g. in myocardial infarction,unstable angina, thrombosis-based stroke and peripheral arterialthrombosis), and systemic embolism usually from the atrium during atrialfibrillation or from the left ventricle after transmural myocardialinfarction, or caused by congestive heart failure; prophylaxis ofreocclusion (i.e., thrombosis) after thrombolysis, percutaneoustrans-luminal angioplasty (PTA) and coronary bypass operations; theprevention of rethrombosis after microsurgery and vascular surgery ingeneral.

Further indications include the therapeutic and/or prophylactictreatment of disseminated intravascular coagulation caused by bacteria,multiple trauma, intoxication or any other mechanism; anticoagulanttreatment when blood is in contact with foreign surfaces in the bodysuch as vascular grafts, vascular stents, vascular catheters, mechanicaland biological prosthetic valves or any other medical device; andanticoagulant treatment when blood is in contact with medical devicesoutside the body such as during cardiovascular surgery using aheart-lung machine or in haemodialysis; the therapeutic and/orprophylactic treatment of idiopathic and adult respiratory distresssyndrome, pulmonary fibrosis following treatment with radiation orchemotherapy, septic shock, septicemia, inflammatory responses, whichinclude, but are not limited to, edema, acute or chronic atherosclerosissuch as coronary arterial disease and the formation of atheroscleroticplaques, cerebral arterial disease, cerebral infarction, cerebralthrombosis, cerebral embolism, peripheral arterial disease, ischaemia,angina (including unstable angina), reperfusion damage, restenosis afterpercutaneous trans-luminal angioplasty (PTA) and coronary artery bypasssurgery.

The compounds of Formula I can also be used in the treatment of canceror rheumatoid arthritis.

Testing

The ability of the compounds of this invention to inhibit factor VIIaand Xa can be tested in vitro and in vivo assays described in biologicalassays Example 1 and 2 below.

Administration and Pharmaceutical Compositions

In general, the compounds of this invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the compound of this invention, i.e., the active ingredient,will depend upon numerous factors such as the severity of the disease tobe treated, the age and relative health of the subject, the potency ofthe compound used, the route and form of administration, and otherfactors.

Therapeutically effective amounts of compounds of Formula I may rangefrom approximately 0.01-50 mg per kilogram body weight of the recipientper day; preferably about 0.1-20 mg/kg/day. Thus, for administration toa 70 kg person, the dosage range would most preferably be about 7 mg to1.4 g per day.

In general, compounds of this invention will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral orparenteral using a convenient daily dosage regimen, which can beadjusted according to the degree of affliction. Oral compositions cantake the form of tablets, pills, capsules, semisolids, powders,sustained release formulations, solutions, suspensions, elixirs,aerosols, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area i.e., decreasing particle size.For example, U.S. Pat No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a crosslinked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 mn) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

The compositions are comprised of in general, a compound of Formula I incombination with at least one pharmaceutically acceptable excipient.Acceptable excipients are non-toxic, aid administration, and do notadversely affect the therapeutic benefit of the compound of Formula I.Such excipient may be any solid, liquid, semi-solid or, in the case ofan aerosol composition, gaseous excipient that is generally available toone skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 18th ed., 1990).

The amount of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt% of a compound of Formula I based on the total formulation, with thebalance being one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 1-80 wt %.Representative pharmaceutical formulations containing a compound ofFormula I are described below.

The compounds of Formula I can be administered alone or in combinationwith other compounds of Formula I or in combination with one or moreother active ingredient(s). For example, a compound of Formula I can beadministered in combination with another anticoagulant agent(s)independently selected from a group consisting of a thrombin inhibitor,a factor IXa, and a factor Xa inhibitor. Preferably, the thrombininhibitor is Inogatran®, Melagatran® or prodrugs thereof which aredisclosed in PCT Application Publication Nos. WO 94/29336 and WO97/23499, the disclosures of which are incorporated herein by referencein their entirety. Factor Xa inhibitors that may be used in thecombination products according to the invention include those describedin Current Opinion in Therapeutic Patents, 1993, 1173-1179 and ininternational patent applications WO 00/20416, WO 00/12479, WO 00/09480,WO 00/08005, WO 99/64392, WO 99/62904, WO 99/57096, WO 99/52895, WO99/50263, WO 99/50257, WO 99/50255, WO 99/50254, WO 99/48870, WO99/47503, WO 99/42462, WO 99/42439, WO 99/40075, WO 99/37304, WO99/36428, WO 99/33805, WO 99/33800, WO 99/32477, WO 99/32454, WO99/31092, WID 99/26941, WO 99/26933, WO 99/26932, WO 99/26919, WO99/26918, WO 99/25720, WO 99/16751, WO 99/16747, WO 99/12935, WO99/12903, WO 99/11658, WO 99/11617, WO 99/10316, WO 99/07732, WO9/07731, WO 99/05124, WO 99/00356, WO 99/00128, WO 99/00127, WO99/00126, WO 9/00121, WO 98/57951, WO 98/57937, WO 98/57934, WO98/54164, WO 98/46591, WO 98/31661, WO 98/28282, WO 98/28269, WO98/25611, WO 98/24784, WO 98/22483, WO 98/16547, WO 98/16525, WO98/16524, WO 98/16523, WO 98/15547, WO 98/11094, WO 98/07725, WO98/06694, WO 98/01428, WO 7/48706, WO 97/46576, WO 97/46523, WO97/38984, WO 97/30971, WO 97/30073, WO 97/29067, WO 97/24118, WO97/23212, WO 97/21437, WO 97/08165, WO 97/05161, WO 96/40744, WO96/40743, WO 96/40679, WO 96/40100, WO 96/38421, WO 96/28427, WO96/19493, WO 96/16940, WO 95/28420, WO 94/13693, WO 00/24718, WO99/55355, WO 99/51571, WO 99/40072, WO 99/26926, WO 98/51684, WO97/48706, WO 97/24135, WO 97/11693, WO 00/01704, WO 00/71493, WO00/71507, WO 00/71508, WO 00/71509, WO 00/71511, WO 00/71512, WO00/71515, WO 00/71516, WO 00/13707, WO 00/31068, WO 00/32590, WO00/33844, WO 00/35859, WO 00/35886, WO 00/38683, WO 00/39087, WO00/39092, WO 00/39102, WO 00/39108, WO 00/39111, WO 00/39117, WO00/39118, WO 00/39131, WO 00/40548, WO 00/40571, WO 00/40583, WO00/40601, WO 00/47207, WO 00/47553, WO 00/47554, WO 00/47563, WO00/47578, WO 00/51989, WO 00/53264, WO 00/59876, WO 00/59902, WO00/71510, WO 00/76970, WO 00/76971, WO 00/78747, WO 01/02356, WO01/02397, WO 01/05784, WO 01/09093, WO 01/12600, WO 01/19788, WO01/19795, WO 01/19798, WO 93/15756, WO 94/17817, WO 95/29189, WO96/18644, WO 96/20689, WO 96/39380, WO 97/22712, WO 97/36580, WO97/36865, WO 97/48687, WO 98/09987, WO 98/46626, WO 98/46627, WO98/46628, WO 98/54132, WO 99/07730, WO 99/33458, WO 99/37643 and WO99/64446; in U.S. Pat. Nos. 6,034,093, 6,020,357, 5,994,375, 5,886,191,5,849,519, 5,783,421, 5,731,315, 5,721,214, 5,693,641, 5,633,381,5,612,378, 6,034,127, 5,670,479, 5,658,939, 5,658,930, 5,656,645,5,656,600, 5,639,739, 5,741,819, 6,057,342, 6,060,491, 6,080,767,6,087,487, 6,140,351, 6,395,731, and 5,646,165; in Japanese patentapplications Nos. JP 99152269, JP 10017549, JP 10001467, JP 98017549, JP00178243, JP 11140040, JP 12143623, JP 12204081, JP 12302765, JP 6327488and JP 98001467; in European patent applications EP 937 723, EP 937 711,EP 874 629, EP 842 941, EP 728 758, EP 540 051, EP 419 099, EP 686 642,EP 1 016 663 and EP 529 715; and in German patent applications Nos. DE19845153, DE 19835950, DE 19743435, DE 19829964, DE 19834751, DE19839499, DE19900355, DE19900471 and DE 19530996, the specific andgeneric disclosures in all of which documents are hereby incorporated byreference.

Factor Xa inhibitors also include those disclosed in internationalpatent applications WO 96/10022, WO 97/28129, WO 97/29104, WO 98/21188,WO 99/06371, WO 99/57099, WO 99/57112, WO 00/47573, WO 00/78749, WO99/09027 and WO 99/57113, the specific and generic disclosures in all ofwhich documents are hereby incorporated by reference, as well as4-{4-[4-(5-chloroindol-2-ylsulfonyl)piperazine-1-carbonyl]phenyl}-pyridine-1-oxide and pharmaceuticallyacceptable derivatives thereof. Preferred Factor Xa inhibitors includeantistatin, tick anticoagulant protein and those known as SQ-311 andSQ-315 (see international patent application WO 98/57951); SN-292 (seeinternational patent application WO 98/28282); SN-429 and SN 116 (seeinternational patent application WO 98/28269); RPR-208707 (seeinternational patent application WO 98/25611 at Example 48); XU-817 (seeinternational patent application WO 98/01428); SF-324 and SF-303 (seeinternational patent application WO 97/23212); YM 60828 (seeinternational patent application WO 96/16940 at Example 75); FACTOREX(see U.S. Pat. No. 5,783,421); SF-324 (see European patent applicationEP 874 629); DX9065A (see European patent application EP 540 051 atExample 39);1-(4-carbamimidoylbenzyl)-4-(6-chloronaphthalene-2-ylsulfonyl)-piperazin-2-one(see JP 12204081 at Example 2); M55555 (see international patentapplication WO 99/33805 at Example 39); DPC423(1-(3-carbamimidoylphenyl)-2-2′-aminolsulfonyl[1,1-biphenyl]-4-ylaminocarbonyl)-4-bromopyrrole,see international patent application WO 98/28269);3-(3,5-difluoro-6-[3-(4,5dihydro-1-methylimidazol-2-yl)-phenoxy]-4-[2,3-dihydroxy-propoxy]-pyridin-2-yloxy)-4-hydroxybenzamidine(see international patent application WO 00/31068); ZK-807834 (seeinternational patent application WO 7/29067);1,4-diaza-4-(6-chloronaphthalene-2-ylsulfonyl)-6-(methoxymethyl)-7-oxa-1′-(pyridin-4-yl)spiro[bicyclo-[4-3.0]-nonane-8,4′-piperidine]-2-one(see international patent application WO 01/02397);(S)-1-(4-aminoquinazolin-7-ylmethyl)-4-[2-5-chlorothien-2-yloxy)acetyl]-3-methoxy-methylpiperazin-2-one(see international patent application WO 00/32590);3-2-[4-(2-aminosulfonyl-phenyl)benzoylphenoxy)-benzamidine (seeinternational patent application WO 01/19788); and4-(2-[4-(5-chloroindol-2-yl-sulfonyl)-2-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl-carbonyl)-thiazol-5-yl)pyridineN-oxide (see Japanese patent application No. JP 12143623); as well asthe compounds of Example 7 of international patent application WO98/21188, of Examples 3 and 6 of WO 99/57113, of Example 6 ofinternational patent application WO 00/78747, of Examples 188, 211 and167 of U.S. Pat. No. 6,080,767, of Examples 40, 54 and 55 ofinternational patent application WO 99/33805, of Examples 5, 6, 8, 9,10, 11, 12, 13, 15, 16 and 17 of international patent application WO01/05784, of Examples 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 22,23, 25, 26, 28, 29, 30, 31, 32, 33, 34, 38, 39, 40, 41, 42 and 43 ofinternational patent application WO 01/12600, and of Examples 802 and877 of international patent application WO 00/35886. Other anticoagulantagents that can be used in the combination therapy are those disclosedin U.S. Patent Applications Publication Nos. 20020065303, 20020061842,20020058677, 20020058657, 20020055522, 20020055469, 20020052368,20020040144, 20020035109, 20020032223, 20020028820, 20020025963,20020019395, 20020019394, 20020016326, 20020013314, 20020002183,20010046974, 20010044537, 20010044536, 20010025108, 20010023292,20010023291, 20010021775, 20010020020033, 20010018423, 20010018414, and20010000179, which are incorporated herein by reference in theirentirety.

Suitable formulations for use in administering melagatran andderivatives (including prodrugs) thereof are described in theliterature, for example as described in inter alia international patentapplications WO 94/29336, WO 96/14084, WO 96/16671, WO 97/23499, WO97/39770, WO 97/45138, WO 98/16252, WO 99/27912, WO 99/27913, WO00/12043 and WO 00/13671, the disclosures in which documents are herebyincorporated by reference.

Similarly, suitable formulations for use in administering Factor Xainhibitors and derivatives (including prodrugs) thereof are described inthe literature, for example as described in the prior art documentsrelating to Factor Xa inhibitors that are mentioned hereinbefore, thedisclosures in which documents are hereby incorporated by reference.Otherwise, the preparation of suitable formulations, and in particularcombined preparations including both melagatran/derivative and Factor Xainhibitor/derivative may be achieved non-inventively by the skilledperson using routine techniques. The amounts of melagatran, Factor Xainhibitor, or derivative of either, in the respective formulation(s)will depend on the severity of the condition, and on the patient to betreated, as well as the compound(s) which is/are employed, but may bedetermined non-inventively by the skilled person.

Suitable doses of melagatran, Factor Xa inhibitors and derivatives ofeither, in the therapeutic and/or prophylactic treatment of mammalian,especially human, patients may be determined routinely by the medicalpractitioner or other skilled person, and include the respective dosesdiscussed in the prior art documents relating to melagatran (orderivatives (including prodrugs) thereof), and to Factor Xa inhibitors,that are mentioned hereinbefore, the disclosures in which documents arehereby incorporated by reference.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Synthetic Examples Reference 1 Synthesis of2-methoxymethylether-5-fluoro-phenylboronic acid

2-Bromo-4-fluorophenol (25.0 g, 0.13 mol) was dissolved in drydichloromethane (100 mL) and dimethoxymethane (115 mL, 1.30 mol).Phosphorus pentoxide (110.8 g, 0.39 mol) was added portion-wise to thesolution such that the reaction temperature remained below 40° C. Themixture was stirred vigorously at room temperature for 2 hours and thencarefully poured into 1N aqueous NaOH (50 mL). The organic layer wasseparated, washed with water and then brine, dried over anhydrous MgSO₄,filtered and concentrated to give 2-bromofluoro-1-methoxymethoxy-benzene(30.1 g) as a colorless oil.

A 500 mL round bottom flask was charged with a 1.6 M solution ofn-butyllithium in hexanes (100 mL, 0.16 mol) and flushed with nitrogen.The solution was cooled to −78° C. and a solution of2-bromo-4-fluoro-1-methoxymethoxy-benzene (30.1 g, 0.13 mol) in drytetrahydrofuran (50 mL) was added dropwise over one hour. The mixturewas stirred at −78° C. and then trimethylborate (20 mL, 0.175 mol) wasadded very slowly via syringe. The reaction was allowed to graduallywarm to room temperature and after two hours the mixture was poured intoice. The mixture was acidified to pH 4 with 5% aqueous citric acid andextracted with ethyl acetate (×3). The combined organic extracts werewashed with water and brine, dried over MgSO₄ and filtered. The solventwas evaporation under reduced pressure and the residue wasrecrystallized from hexanes give 2-methoxymethoxy-5-fluorophenylboronicacid (18.9 g).

Reference 2 Synthesis of tert-butyl2-bromo-5-chloro-6-cyano-pyridin-3-yl-carbamate

2-Hydroxy-5-nitropyridine (50 g, 357 mmol) and N-chlorosuccinimide (55g, 410 mmol) were suspended in anhydrous DMF (150 mL). The suspensionwas stirred at room temperature for 18 hours. The resulting homogeneousreaction mixture was diluted by the slow addition of water (750 mL),which resulted in a pale yellow precipitate. The solids were isolatedvia filtration and dried under high vacuum to provide3-chloro-5-nitro-2-hydroxypyridine (59 g, 95% yield).

3-Chloro-5-nitro-2-hydroxy-pyridine (20 g) was added in small portionsto thionylchloride (200 mL) under vigorous stirring. The suspension washeated to 100° C. within 1 hour, stirred at 100° C. for 1 hour and thencooled to room temperature. The solvent was removed under reducedpressure and the residue was dissolved in ethyl acetate. The solutionwas washed with water (3×200 mL) and the organic layer was dried overMgSO₄. The solvent was removed under reduced pressure to give2,3-dichloro-5-nitropyridine (18 g) was obtained as a pale yellow solid.

A solution of 2,3dichloro-5-nitropyridine (9.75 g) and potassium iodide(29 g) in acetic acid (120 mL, degassed with nitrogen) was heated to100° C. for 1.5 hours under nitrogen. The brown solution was cooled toroom temperature and then ethyl acetate (300 mL) added. The organicphase was separated and washed with water (2×100 mL) and dilute aqueoussodium sulfite (100 mL). Evaporation of the solvent gave crystalline3-chloro-2-iodo-5-nitro-pyridine (13.11 g).

A suspension of copper cyanide (7 g) and3-chloro-2-iodo-5-nitro-pyridine (7 g) in acetonitrile (200 mL) washeated to 80° C. within 1 hour and stirred at 80° C. for 5 hours. Thesolvent was evaporated and the residue was filtered in ethyl acetateover silicon dioxide gave 3-chloro-2-cyano-5-nitro-pyridine (4.26 g).

A solution of tin chloride (52 g) and 3-chloro-2-cyano-5-nitro-pyridine(10.3 g) was stirred in ethyl acetate (200 mL) at room temperature for10 minutes and at 70° C. for 4 hours. The solution was cooled to roomtemperature and diluted with ethyl acetate (500 mL). Sodium bicarbonate(100 g) added in four portions to the mixture within 4 hours. Themixture was stirred vigorously for 20 hours. The suspension was filteredand the filtrate was washed with saturated aqueous sodium bicarbonatesolution. The solvent was evaporated to give5-amino-3-chloro-2-cyanopyridine (4.34 g) as an off-white powder.

Step (f)

Bromine (7.22 g) was added to a stirring mixture of5-amino-3-chloro-2-cyanopyridine (4.61 g) and sodium acetate (4.81 g) inanhydrous acetic acid (150 mL) at room temperature. The mixture wasstirred at 60° C. for 2 hours. The solvents and excess bromine wereevaporated and the residue was recrystalliezed from ethyl acetate togive 5-amino-6-bromo-3-chloro-2-cyano-pyridine (6.23 g).

5-Amino-6-bromo-3-chloro-2-cyano-pyridine (1.6 g) was dissolved intetrahydrofuran (5 mL) at room temperature. N,N-dimethylaminopyridine(0.5 g) followed by di-tert-butyl dicarbonate (3.78 g) in small portionswere added to the solution and the mixture was stirred at roomtemperature for 30 minutes. The solvent was removed by evaporation andthe residue was dissolved in dicloromethane (60 mL). Trifluoroaceticacid (1 g) was added to the solution and the mixture was stirred for 1hour. The solvent was removed by evaporation and product was purifiedfrom the residue by column chromatography (EtOAc/hexanes 1/1) to givetert-butyl 2-bromo-5-chloro-6-cyano-pyridin-3-yl-carbamate (1 g). MS(obs.): 333 (M+1).

Reference 3 Synthesis of 5-cyano-2-methoxybenzeneboronic acid

3-Bromo4-methoxybenzonitrile (3.0 g, 14.2 mmol, 1.0 eq) was dissolved inanhydrous tetrahydrofuran (10 mLs). The solution cooled at −10° C. andstirred while isopropylmagnesium chloride (17.7 mmol, 8.8 mLs, 2.0 M inTHF, 1.25 eq.) was added. The mixture was stirred for 1 hour and thentrimethyl borate (1.87 g, 17.7 mmol, 2.0 mL) was added dropwise. Themixture was allowed to warm slowly to room temperature for 1 hour. Thesolvent was evaporated and the residue was partitioned between 5% citricacid and ethyl acetate. The organic layer was separated, washed withwater and brine, dried over anhydrous magnesium sulfate and concentratedto a minimum volume under reduced pressure. The residue wasrecrystallized from hexanes to give 5-cyano-2-methoxybenzeneboronic acid(2.48 g, 99%) as a fluffy white powder.

Reference 4 Lithium 2-aminoethanesulfonate

Lithium hydroxide monohydrate (0.42 g, 0.10 mol) was dissolved in water(15 mL) and the solution was treated with 2-amino-ethanesulfonic acid(1.25 g, 0.10 mol). The mixture was stirred until all solids dissolvedand then for an additional 30 minutes. The water solvent was evaporatedoff in vacuo and the resulting wet solid was heated at 70° C. undervacuum (1 Torr) overnight to give lithium 2-aminoethanesulfonate as adry, free-flowing colorless solid.

Reference 5 tert-Butyl 6-amino-2-tert-butoxycarbonylamino-hexanoate

tert-Butyl 2-amino-6-benzyloxycarbonylamino-hexanoate (1.0 g, 2.68 mmol)was dissolved in N,N-dimethylformamide (50 mL) and then triethylamine(5.35 mmol, 0.75 mL) followed by N-(tert-butoxycarbonyloxy)succinimide(0.72 g, 3.35 mmol) was added to the solution. The mixture was stirredovernight and then concentrated. The product was purified from theresidue by silica gel chromatography (20% MeOH/chloroform) to givetert-butyl6-benzyloxycarbonylamino-2-tert-butoxycarbonylamino-hexanoate. Thetri-protected product was reduced on a Parr hydrogenator (50 psi) toremove the benzyloxycarbonyl protecting group. The solvents were removedto give tert-butyl 6-amino-2-tert-butoxycarbonylamino-hexanoate (0.65 g,80%).

Reference 6 3-Bromo-N-tert-butyl-4-methoxybenzenesulfonamide

1-Bromo-2-methoxy-benzene (1.87 g, 10.0 mmol) was dissolved inchloroform (5 mL) and the solution was cooled in an ice-salt bath to −5°C. to 0° C. The cooled solution was carefully charged withchlorosulfonic acid (2.0 mL, 30.0 mmol) over 30 minutes and the mixturewas allowed to warm to room temperature over 1 hour. The mixture thenwas poured onto chopped ice and transferred to a separatory funnel. Theaqueous layer was separated and extracted (×2). The combined organiclayers were dried and concentrated to give3-bromo-4-methoxyphenylsulfonyl chloride (2.80 g, 98%).

3-Bromo4-methoxyphenylsulfonyl chloride (2.80 g, 9.8 mmol) was dissolvedin dichloromethane (30 mL) and the solution was treated withtriethylamine (1.76 mL, 12.6 mmol), followed by the dropwise addition oft-butylamine (1.33 mL, 12.6 mmol). The mixture was allowed to stand for2 hours and then was poured onto a mixture of 5% citric acid solutionand dichloromethane. The organic layer was separated and the aqueouslayer was extracted with dichloromethane (×2). The combined organiclayers were dried and concentrated. Crystallization of the crude solidfrom ethyl acetate/hexane gave3-bromo-N-tert-butyl-4-methoxybenzenesulfonamide (2.43 g, 77%).

Reference 7 Synthesis of1-[3-bromo-4-(2-methoxyethoxymethoxy)benzyl]-3-tert-butylurea

Diisopropylethylamine (21.8 mL, 151.5 mmol) was added slowly to amagnetically stirred solution of 3-bromo-4-hydroxybenzonitrile (10 g,50.5 mmol) and 2-methoxyethoxymethyl chloride (6.9 mL, 60.6 mmol) indichloromethane (100 mL) and the mixture was stirred at room temperaturefor 30 minutes. The mixture was washed with 5% citric acid solutionuntil the washings were acidic, dried and concentrated. Product waspurified from the residue by chromatography (silica gel, 30% ethylacetate/hexanes) gave 3-bromo-4-(2-methoxyethoxymethoxy)-benzonitrile(11.5 g).

Borane-tetrahydrofuran complex (280 mL, 1 M, 280 mmol) was added to amagnetically stirred solution of3-bromo-4-(2-methoxyethoxymethoxy)-benzonitrile (10 g, 35 mmol) intetrahydrofuran (20 mL) and the reaction mixture was refluxed for 30minutes. The mixture was cooled to 0° C. and 1 N HCl was added veryslowly until the pH was acidic. The tetrahydrofuran was removed byevaporation and the residual aqueous layer was washed with ethyl ether.The aqueous extract was basified with 2 N sodium hydroxide untilalkaline pH and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous sodium sulfate and concentratedby evaporation to give 3-bromo-4-(2-methoxy-ethoxymethoxy)benzylamine(5.6 g).

tert-Butylisocyanate (2.9 mL, 25.5 mmol) followed by triethylamine (9.8mL, 68 mmol) was added to a magnetically stirred solution of3-bromo-4-(2-methoxyethoxymethoxy)benzyl-amine (5 g, 17 mmol) in DMF (50mL) and the mixture was stirred at room temperature for 15 minutes. Themixture was diluted with water (10 mL) and the dilution was extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated by evaporation. Product waspurified from the residue by chromatographic (silica gel) employing 100%ethyl acetate as eluent to give1-[3-bromo4-(2-methoxyethoxymethoxy)benzyl]-3-tert-butylurea (5.3 g).

Reference 8 Synthesis of 3-bromo-2-hydroxybenzaldehyde

2-Bromophenol (2 g, 11.5 mmol) was dissolved in anhydrous acetonitrile(25 mL) and the solution was charged with anhydrous (<1.5% water)magnesium chloride (4.4 g, 46 mmol) and dry triethylamine (12.5 mL, 86.3mmol). The mixture was stirred for 5 minutes and paraformaldehyde (2.8g, 92 mmol) was added. The mixture was heated to a gentle reflux for 1to 3 hours and then cooled. The mixture was poured onto an ether/5%citric acid mixture and the ether layer separated. The ether layer waswashed with water, brine, dried over anhydrous sodium sulfate andconcentrated by evaporation. Product purified from the residue bychromatography on silica gel employing 30% ethyl acetate/hexanes to give3-bromo-2-hydroxybenzaldehyde (1.6 g).

Proceeding as in Reference 8, but substituting4-hydroxyphenylacetonitrile (2.09 g, 15 mmol) and formaldehyde (3.6 g,120 mmol) gave 3-formyl-4-hydroxyphenylacetonitrile (1.8 g).

Proceeding as in Reference 8, but substituting methyl 4-hydroxybenzoate(30.4 g, 0.20 mol, 1.0 eq.) and paraformaldehyde (42.0 g, 1.40 mol, 7.0eq.), gave methyl 3-formyl-4-hydroxybenzoate (16.7 g) as a white solid.

Proceeding as in Reference 8, but substituting methyl4-hydroxyphenylacetate (42.9 g, 0.258 mol) and paraformaldehyde (77.5 g,2.58 mole), gave methyl 3-formyl-4-hydroxy-phenyl-acetate (50.0 g,˜100%).

Proceeding as in Reference 8, but substitutingmethyl-3-bromo-4-hydroxyphenylacetate, gavemethyl-3-formyl-4-hydroxy-5-bromophenylacetate.

Reference 9 3-bromo-5-fluoro-2-hydroxybenzaldehyde

N-bromosuccinimide (1.51 g, 8.52 mmol) was added to a magneticallystirred solution of 5-fluoro-2-hydroxybenzaldehyde (1 g, 7.1 mmol) inDMF (10 mL) and the mixture was stirred at room temperature for 5 hour.The mixture was diluted with ethyl acetate and the organic layer waswashed with 5% citric acid, brine, dried over anhydrous sodium sulfateand concentrated by evaporation. Product was purified from the residueby chromatography over silica gel employing 50% ethyl acetate/hexanes togive 3-bromo-5-fluoro-2-hydroxybenzaldehyde (1.2 g).

Proceeding as in Reference 9, but substituting3-formyl-4-hydroxyphenylacetonitrile (1 g, 6.2 mmol) andN-bromosuccinimide (1.7 g, 9.3 mmol), gave3-bromo-5-formyl-4-hydroxyphenylacetonitrile (1.2 g).

Proceeding as in Reference 9, but substituting 5-methyl salicylaldehyde(3 g, 22 mmol) and N-bromosuccinimide (4.7 g, 26.4 mmol), gave3-bromo-2-hydroxy-5-methylbenzaldehyde (3.6 g).

Proceeding as in Reference 9, but substituting methyl3-formyl4-hydroxybenzoate (12.0 g, 66.6 mmol, 1 eq.) andN-bromosuccinimide (12.45 g, 69.9 mmol, 1.05 eq.) gave methyl3-bromo-5-formyl-4hydroxybenzoate (12.6 g) as a white solid.

Proceeding as in Reference 9, but substituting methyl3-formyl4-hydroxy-phenyl-acetate (50 g, 0.258 mol) and N-bromosuccininde(45.92 g, 0.258 mole), gave methyl3-bromo-5-formyl4-hydroxyphenylacetate (56.4 g, 80%) as a yellowamorphous solid.

Reference 10 Synthesis of 3-bromo-4-hydroxyphenylacetate

Methyl 4-hydroxyphenylacetate (10.5 g, 63.0 mmol) was dissolved inacetic acid (200 mL) and the solution was stirred while bromine (150 mL,0.463 M in acetic acid, 69.5 mmol) was added over 60 minutes. Themixture was stirred overnight and then concentrated by evaporation.Product was purified from the residue over 300 g of silica gel(hexanes/ethyl acetate 5:1) to give methyl3-bromo-4-hydroxyphenylacetate (11.9 g).

Proceeding as in Reference 14, but substituting 4-methoxyphenylaceticacid (16.6 g, 0.1 mol) and bromine (16.0 g, 0.1 mol), gave3-bromo-4-methoxyphenylacetic acid (24.24 g, 98%) as a yellow powder.

Reference 11 Synthesis of3-bromo-N-butyl-5-formyl-4-methoxy-benzenesulfonamide

5-Bromo-3-formyl-4-methoxybenzoic acid (480 mg, 1.84 mmol) was dissolvedin anhydrous tetrahydrofuran (20 mL) and the solution was flushed withdry nitrogen for 5 minutes. Oxalyl chloride (1.2 mL, 2.4 mmol, 1.3 eq)was added slowly to the solution while vigorous stirring and then acatalytic amount of dry dimethylformamide was added. The mixture wasstirred for 1 hour and then concentrated by rotary evaporation and driedon high vacuum to give 5-bromo-3-formyl-4-methoxybenzoyl chloride (501mg) as yellow crystals.

5-Bromo-3-formylmethoxybenzoyl chloride (501 mg, 1.8 mmol) was dissolvedin in dichloromethane (5 mL) and the solution was added dropwise to avigorously stirring solution of N-butylsulfonamide (272 mg, 2.0 mmol),triethylamine (2.5 mmol) and a catalytic amount ofN,N′-diethylaminopyridine (10 mL in dichloromethane). The mixture wasstirred at room temperature until the reaction was complete andconcentrated under reduced pressure. The residue was partitioned between5% citric acid and ethyl acetate. The organic layer was washed withwater and brine, dried over anhydrous magnesium sulfate and the filtratewas evaporated to give3-bromo-N-butyl-5-formyl-4-methoxy-benzenesulfonamide as a white solid(650 mg).

Reference 12 Synthesis of3-bromo-2-(2-methoxy-ethoxymethoxy)benzaldehyde

3-Bromo-2-hydroxybenzaldehyde (1.5 g, 7.5 mmol) was dissolved indichloromethane (25 mL) and diisopropylethylamine (2 mL, 11.3 mmol) wasadded to the solution. The mixture was stirred while2-methoxyethoxymethyl chloride (0.94 mL, 8.3 mmol) was added dropwise.The mixture was stirred for 1 hour and then washed with 5% citric acidsolution (5 mL) until the washings were acidic, dried and concentratedby evaporation. Product was purified from the residue by chromatography(silica gel, 30% ethyl acetate/hexanes) to give3-bromo-2-2-methoxy-ethoxymethoxy)benzaldehyde (1.7 g).

Proceeding as in Reference 12, but substituting3-bromo-5-fluoro-2-hydroxybenzaldehyde, gave3-bromo-5-fluoro-2-(2-methoxy-ethoxymethoxy)-benzaldehyde; andsubstituting 3-bromo-5-formyl-4-hydroxyphenylacetonitrile (1.2 g, 5mmol) to give3-bromo-5-formyl-4-(2-methoxy-ethoxymethoxy)-phenyl-acetonitrile (1.4g).

Proceeding as in Reference 12, but substituting methyl3-bromo-5-formyl-4-hydroxybenzoate (12.6 g, 48.6 mmol, 1.0 eq.) andmethoxyethoxymethyl chloride (6.8 mL, 7.26 g, 58.3 mmol, 1.2 eq.), gavemethyl 3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-benzoate (16.2 g) asa colorless oil which solidified upon standing.

Proceeding as in Reference 12, but substituting methyl3-bromo-4-hydroxyphenylacetate (22.33 g, 91.14 mmol) and2-methoxyethoxymethyl chloride (13.62 g, 12.49 mL, 0.11 mol), gave3-bromo-4-methoxyethoxymethoxy)-phenylacetate (32.67 g).

Proceeding as in Reference 12, but substituting methyl3-bromo-5-formyl-4-hydroxyphenylacetate (27.32 g, 0.10 mole) and2-methoxyethoxymethyl chloride (0.125 mol, 14.3 mL), gave methyl3-bromo-5-formyl-4(2-methoxyethoxymethoxy)-phenylacetate (31.4 g (87 %).

Reference 13 Synthesis of3-bromo-2-(methoxyethoxymethoxy)-5-(1-(methoxyethoxymethyl)-1H-tetrazol-5-yl)benzaldehyde

A solution of 3-bromo-2-hydroxy-5-(1H-tetrazol-5-yl)benzaldehyde indichloromethane (25 mL) was treated with diisopropylethylamine (1.2 mL,6.4 mmol) and 2-methoxyethoxymethyl chloride (0.72 mL, 6.4 mmol) under astream of nitrogen and the mixture was stirred at room temperature for 2hours. Workup involved rotovaping off most of the dichloromethane,followed by usual extractive workup with ethyl acetate and 5% aqueouscitric acid. Collection and drying of the organic extracts gave aregioisomeric mixtures of3-bromo-2-(methoxyethoxymethoxy)-5-(1-(methoxyethoxymethyl)-1H-tetrazol-5-yl)benzaldehyde(0.93 g) as an oil.

Reference 14 Synthesis of methyl 4-benzyloxy-3-bromo-5-formyl-benzoate

Methyl 3-bromo-5-formyl-4-hydroxybenzoate (11.5 g, 44.39 mmol) wasdissolved in acetone (100 mL) and then benzylbromide (8.35 g, 48.83mmol) and potassium bicarbonate (6.74 g, 48.83 mmol) were added. Themixture was stirred overnight and the organic layer was washed withwater. The organic layer was separated, dried over MgSO₄ andconcentrated. Product was purified from the residue by flash silica gelchromatography to give methyl 4-benzyloxy-3-bromo-5-formyl-benzoate(10.0 g).

Reference 15 Synthesis of tert-butyl (3-bromo-benzyl)carbamate

A mixture of 3-aminomethylbromobenzene (22.11 g, 99.5 mmol),di-tert-butyl dicarbonate (26.07 g, 119.45 mmol), sodium hydroxide (8.76g, 219 mmol) in tetrahydrofuran (75 mL) and water (100 mL) were stirredat room temperature for 30 minutes. Extraction and work-up withmethylene chloride and water, followed by drying gave tert-butyl(3-bromo-benzyl)carbamate (34.9 g).

Proceeding as in Reference 15, but substituting3-bromo-4-(2-methoxyethoxymethoxy)benzylamine (2.40 g, 8.27 mmol) anddi-tert-butyl dicarbonate (3.56 g, 16.3 mmol), gave tert-butyl[3-bromo4-(2-methoxyethoxymethoxy)-benzyl]carbamate (2.36 g).

Reference 16 Synthesis ofN-acetyl-5-bromo-3-formyl-4-methoxybenzenesulfonamide

A 100 mL round-bottom flask was charged with5-bromo-3-formyl-4-methoxy-benzenesulfonamide (586 mg, 2.0 mmol)dissolved in dichloromethane (40 mL) and the solution was stirredvigorously while triethylamine (252 mg, 2.50 mmol) was added, followedby acetic anhydride (224 mg, 2.2 mmol) and a catalytic amount ofN,N-dimethylaminopyridine. The mixture was stirred for 1 hour and thenconcentrated by evaporation. The residue was partitioned between 5%citric acid and ethyl acetate. The organic layer was separated, washedwith water and brine and dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to giveN-acetyl-5-bromo-3-formyl-4-methoxybenzenesulfonamide (616 mg) as awhite solid.

Reference 17 Synthesis of methyl-3-bromo-4-hydroxyphenylacetate

3-Bromo-4-hydroxyphenylacetic acid (12.0 g, 0.052 mol) was dissolved inmethanol and the solution was stirred at room temperature while thionylchloride (ten drops) was added. The mixture was stirred for two hoursand then concentrated under reduced pressure. The residue was taken upin saturated aqueous sodium bicarbonate and the solution extracted withdiethyl ether (×3). The organic layers were collected, washed with waterand brine, dried over MgSO₄ and concentrated in vacuo to givemethyl-3-bromo-4-hydroxyphenylacetate as a golden oil (12.6 g).

Reference 18 Preparation of 3-bromo-5-formyl-4-methoxybenzenesulfonamide

3-Bromo-2-hydroxy-benzaldehyde (27 g, 134 mmol), prepared as describedin N. Hofsloekken, L. Skatteboel, “Convenient Method for theortho-Formulation of Phenols”, Acta Chemica Scandinavica, 1999, v. 53,p. 258-262), was dissolved in dimethylformamide (150 mL) and then cesiumcarbonate (54.7 g, 170 mmol) was added to the solution portionwise. Themixture was stirred for 30 minutes and then methyl iodide (28.5 g, 201mmol) was added. The mixture was stirred for 20 hours and poured intowater. The product was extracted with ethyl ether and the organic layerwas washed with water and brine, dried over magnesium sulfate andconcentrated to give 3-bromo-2-methoxybenzaldehyde (28 g).

3-Bromo-2-methoxybenzaldehyde (28 g, 130 mmol) was combined withtrimethylorthoformate (27.5 g, 28.6 mL, 260 mmol) in methanol (150 mL)and then chlorosulfonic acid (0.5 mL) was added dropwise to the mixture.The mixture was stirred for 3 hours and then concentrated byrotoevaporation. The residue was partitioned between ethyl ether and 5%aqueous sodium bicarbonate and the organic layer was separated, washedwith water and brine, dried over sodium sulfate and concentrated to give1-bromo-3-dimethoxymethyl-2-methoxybenzene (27.5 g).

1-Bromo-3-dimethoxymethyl-2-methoxybenzene (9 g, 35 mmol) was dissolvedin methylene chloride (3 mL) and the solution was added dropwise to a 0°C., vigorous stirring solution of chlorosulfonic acid (50 mL). Themixture then was stirred for 3 hours at 0° C. and let stand for 20 hoursat room temperature. The reaction was quenched by pouring the mixtureportionwise onto ice (1 kg). The product was extracted with ethyl etherand the organic layer was washed with cold water (×3) and brine, driedover sodium sulfate, filtered and treated with a stream of gaseousammonia. Product was purified by flash silica column using hexanes/ethylacetate mixture (7:3) as an eluent to give3-bromo-5-formyl-4-methoxybenzenesulfonamide (3.2 g).

Reference 17 Synthesis of N-tert-butyl-3-bromobenzenesulfonamide

tert-Butylamine (3.14 g, 3.0 mmol, 1.1 eq) and triethylamine (5.94 g,58.6 mmol, 1.5 eq.) were dissolved in dichloromethane (20 mL) andstirred at room temperature while 3-bromobenzenesulfonyl chloride (10.0g, 39.1 mmol) was added slowly. The mixture was stirred for 1 hour andthen concentrated by evaporation under reduced pressure. The residue wastaken up in 5% citric acid and ethyl acetate. The organic layer iswashed repeatedly with brine and water, dried over anhydrous magnesiumsulfate and concentrated to give N-tert-butyl-3-bromobenzenesulfonamide(10.94 g) as a white powder.

Reference 18 Synthesis of2-2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde

Bispinacolato diboron (3.3 g, 12.8 mmol) and potassium acetate (3.2 g,32.1 mmol) was added to a stirring solution of3-bromo-2-(2-methoxyethoxymethoxy)benzaldehyde (3.1 g, 10.7 mmol) inanhydrous dioxane (100 mL) and the mixture was heated at 90° C. for 5minutes. The mixture was flushed with nitrogen and thendichloro[1,1′-bix(diphenylphosphino)ferrocene]Palladium (II)dichloromethane adduct (0.218 g, 0.27 mmol) was added and the reactionwas refluxed for 7 to 8 hours. The mixture was cooled to roomtemperature and then diluted with ethyl acetate. The organic layer waswashed with 5% citric acid, brine, dried over anhydrous sodium sulfateand concentrated by evaporation. Product was purified from the residueby chromatography (silica gel) with 100% ethyl acetate to give2-(2-methoxyethoxymethoxy)-3-4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde(40% yield).

Proceeding as in Reference 18, but substituting3-bromo-5-fluoro-2-(2-methoxy-ethoxymethoxy)-benzaldehyde, gave5-fluoro-2-(2-methoxy-ethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde.

Proceeding as in Reference 18, but substituting3-bromo-5-formyl-4-2-methoxy-ethoxymethoxy)-phenyl-acetonitrile, gave[3-formyl-4-(2-methoxy-ethoxymethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrile.

Proceeding as in Reference 18, but substitutingN-tert-butyl-3-bromobenzenesulfonamide (4.4 g, 15.1 mmol) andbispinacolato diboron (5.0 g, 19.7 mmol), gavesN-tert-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide(5.31 g) as peach colored crystals.

Proceeding as in Reference 18, but substituting3-bromo-4-methoxybenzonitrile (4.77 g, 22.5 mmol) andbis(pinacolato)diboron (6.85 g, 27.0 mmol)gave4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile.

Proceeding as in Reference 18, but substituting methyl3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-phenylacetate (5.0 g, 13.8mmol) and bis(pinacolato)diboron (4.22 g) gave methyl3-formyl-4-(2-methoxyethoxy-methoxy)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylacetateand methyl 5-formyl-4-(2-methoxyethoxymethoxy)-phenylacetate in a 2:1ratio.

Proceeding as in Reference 18, but substituting3-bromo-4-methoxyethoxy-methoxybenzonitrile (5.9 g, 20.33 mmol) andbis(pinacolato)diboron (6.2 g, 24.4 mmol), gave4-methoxyethoxymethoxy-3-4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrileas a crude brown oil.

Reference 19 Synthesis of1-tert-butyl-3-[3′-formyl-6,2′-bis-(2-methoxyethoxymethoxy)-biphenyl-3-ylmethyl]-urea

A 2 M solution of potassium carbonate (2.1 mL) was added to amagnetically stirred mixture of1-[3-bromo-4-2-methoxyethoxymethoxy)benzyl]-3-tert-butylurea (1.4 g, 4.1mmol), prepared as in Reference 11, and2-(2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde(42 mL, 0.1 mM in toluene, 4.2 mmol), prepared as in Reference 15. Themixture was flushed with nitrogen and thentetrakis(triphenylphosphine)palladium(0) (118 mg, 0.1025 mmol) wasadded. The mixture was refluxed for 7 hours, cooled and then poured intoa mixture of ethyl acetate and 5% citric acid. The organic phase wasseparated and the aqueous phase was extracted twice more with ethylacetate. The combined organic phase was dried and concentrated byevaporation. Product was purified from the residue by chromatography onsilica gel utilizing 100% ethyl acetate to give1-tert-butyl-3-[3′-formyl-6,2′-bis-(2-methoxyethoxymethoxy)-biphenyl-3-ylmethyl)-urea(1.2 g).

Proceeding as in Reference 19, but substituting1-[3-bromo4-(2-ethoxyethoxymethoxy)benzyl]-3-tert-butylurea (1.0 g, 2.9mmol) and5-fluoro-2-2-methoxy-ethoxymethoxy)-3-4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde(29 mL, 0.1 mM in toluene, 2.9 mmol) gave1-tert-butyl-3-[5′-fluoro-3′-formyl-6,2′-bis-(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]-urea(0.854 g).

Proceeding as in Reference 19, but substituting3-bromo-2-hydroxy-5-methylbenzaldehyde (0.60 g, 2.5 mmol) andN-tert-butyl-3-(4,4,5,5-tetramethyl-(1,3,2]dioxaborolan-2-yl)-benzenesulfonamide(0.846 g, 2.5 mmol), gaveN-tert-butyl-3′-formyl-2′-(2-methoxyethoxymethoxy)-5′-methyl-biphenyl-3-sulfonamide(0.87 g) Proceeding as in Reference 19, but substituting methyl3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-benzoate (2.00 g, 5.76 mmol,1.0 eq.) andN-tert-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide(1.95 g, 5.76 mmol, 1.0 eq.), gave methyl3′-tert-butylsulfamoyl-5-formyl-6-(2-methoxyethoxymethoxy)-biphenyl-3-carboxylate(2.16 g) as a yellow gum.

Proceeding as in Reference 19, but substituting4-benzyloxy-3-bromo-5-formyl-benzoic acid methyl ester (1.0 g, 2.71mmol) and 5-fluoro-2-methoxyphenyl boronic acid (0.691 g, 4.16 mmol),gave 6-benzyloxy-5′-fluoro-5-formyl-2′-methoxybiphenyl-3-carboxylic acidmethyl ester (0.620 g).

Proceeding as in Reference 19, but substituting3-bromo-4-(2-methoxyethoxymethoxy)phenylacetate (2.43 g, 7.28 mmol) and2-(2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzaldehydein toluene (7.28 mmol, 0.1 M, 73 mL), gave methyl[3′-formyl-6,2′-bis(2-methoxyethoxymethoxy)biphenyl-3-yl]acetate (2.42g).

Proceeding as in Reference 19, but substituting3-bromo-N-tert-butyl-4-methoxybenzenesulfonamide (1.45 g, 4.5 mmol) andmethyl3-formyl-4-(2-methoxyethoxy-methoxy)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenylacetate,gave[5′-tert-butylsulfamoyl-5-formyl-2′-methoxy-6-(2-methoxyethoxymethoxy)biphenyl-3-yl]acetate(1.56 g, 77%). LCMS: Calcd 451.53; Obsd (M+23)=474.0, (MH−)=450.1.

Proceeding as in Reference 19, but substituting3-bromo-N-tert-butyl-4-methoxybenzenesulfonamide and methyl3-formyl-4-(2-methoxyethoxy-methoxy)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzoate,gave methyl6-beniyloxy-5′-tert-butylsulfamoyl-5-formyl-2′-methoxy-biphenyl-3-carboxylate.

Proceeding as in Reference 19, but substituting tert-butyl(3-bromo-benzyl)-carbamate (0.9 g, 3.2 mmol) and4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile(0.9 g, 3.5 mmol), gave tert-butyl(5′-cyano-2′-methoxybiphenyl-3-ylmethyl)carbamate (0.73 g, 68%) as whitefoam.

Proceeding as in Reference 19, but substituting3-bromo-2-(methoxyethoxymethoxy)-5-[1-(methoxyethoxymethyl)-1H-tetrazol-5-yl]benzaldehyde(0.93 g, 2.09 mmol) and4-methoxyethoxymethoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile(1.04 g, 3.14 mmol), gave a regioisomeric mixture of3′-formyl-6,2′-methoxyethoxymethoxy)-5-49-(1-methoxyethoxymethyl-1H-tetrazol-5-yl)biphenyl-3-ylcarbonitrile (0.3g).

Proceeding as in Reference 19, but substitutingN-acetyl-3-bromo-5-formyl-4-methoxy-benzenesulfonamide (335 mg, 1.0mmol) andN-tert-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide(373 mg, 1.1 mmol), gaveN-acetyl-N′-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide(242 mg) as a pale yellow oil.

Proceeding as in Reference 19, but substituting3-bromo-N-butyl-5-formyl-4-methoxy-benzenesulfonamide (0.65 g, 1.72mmol) andN-tert-butyl-3-4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide(0.64 g, 1.90 mmol, 1.1 eq.), gaveN-butyl-N′-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide(0.74 g) as on orange oil.

Proceeding as in Reference 19, but substituting2-bromo-6-2-methoxy-ethoxymethoxy)-benzaldehyde provided3′-formyl-4′-methoxyethoxymethoxy)-N-tert-butyl-biphenylsulfonamide.

Proceeding as in Reference 19, but substituting3-bromo-5-formyl-4-methoxy-benzenesulfonamide (0.9 g, 3.1 mmol) and2-methoxybenzene boronic acid (0.51 g, 3.37 mmol), gave5-formyl-6,2′-dimethoxy-biphenyl-3-sulfonamide (0.75 g).

Proceeding as in Reference 19, but substituting3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-nitrobenzene boronicacid, gave 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide.

Proceeding as in Reference 19, but substituting3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-chlorobenzeneboronic acid, gave 3′-chloro-5-formyl-6-methoxy-biphenyl-3-sulfonamide.

Proceeding as in Reference 19, but substituting3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-aminobenzene boronicacid, gave 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.

Proceeding as in Reference 19, but substituting3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-ureidobenzeneboronic acid, gave 5-formyl-6-methoxy-3′-ureido-biphenyl-3-sulfonamide.

Proceeding as in Reference 19, but substituting3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-methoxybenzeneboronic acid, gave 5-formyl-3′,6-dimethoxy-biphenyl-3-sulfonic acidamide.

Proceeding as in Reference 19, but substituting3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-chlorobenzeneboronic acid, gave 3′-chloro-5-formyl-6-methoxy-biphenyl-3-sulfonamide.

Proceeding as in Reference 19, but substituting3-bromo-5-formyl-4-methoxy-benzenesulfonamide and benzene boronic acid,gave 5-formyl-6-methoxy-biphenyl-3-sulfonic acid amide.

Proceeding as in Reference 19, but substituting3-bromo-5-formyl-4-methoxy-benzenesulfonamide and5-cyano-2-methoxy-benzeneboronic acid, gave5′-cyano-5-formyl-6,2′-dimethoxybiphenyl-3-sulfonamide.

Proceeding as in Reference 19, but substitutingmethyl-3-formyl-4-hydroxy-5-bromophenylacetate (2.47 g, 9.0 mmol) and2-methoxymethoxy-5-fluorophenylboronic acid (2.0 g, 10.0 mmol), gavemethyl5′-fluoro-5-formyl-6-hydroxy-2′-methoxymethoxy-biphenyl-3-yl)-acetate(2.2 g, 70%) as a yellow oil which crystallized overnight Proceeding asin Reference 19, but substituting tert-butyl[3-bromo-4-(2-methoxyethoxymethoxy)-benzyl]carbamate (2.3 g, 5.9 mmol)and2-2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde(60 mL, 0.1 M in toluene), gave tert-butyl[3′-formyl-6,2′-bis(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]carbamate(2.96 g).

Reference 20 Synthesis of1-tert-butyl-3-[3′-formyl-2′-hydroxy-5′-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]urea

tert-Butyl (5′-cyano-2′-methoxy-biphenyl-3-yl-methyl)-carbamate (0.73 g,2.16 mmol), prepared as in Reference 19, and azidotributyltin (0.9 mL,3.2 mmol) was dissolved in toluene (5 mL) and the solution was refluxedfor 14 hours. The mixture cooled to room temperature and then workupwith ethyl acetate and 1N HCl gave a slurry. The slurry was dried byrotovap and then triturated with hexanes. The solids were collected byfiltration and treated with hydrobromic acid (48% aqueous, 15 mL). Themixture was refluxed for 14 hours at 120° C. and then diluted with water(50 mL). The dilution was dried by lyophilization to give3′-aminomethyl-5-(1H-tetrawol-5-yl)-biphenyl-2-ol (0.4 g).

3′-aminomethyl-5-(1H-tetrazol-5-yl)-biphenyl-2-ol (0.31 g, 1.16 mmol)was dissolved in dimethylformamide (10 mL) and the solution was treatedwith triethylamine (0.8 mL, 5.8 mmol) and tert-butylisocyanate (0.14 mL,1.27 mmol). The mixture was stirred at room temperature for 2 hours.Workup with ethyl acetate and water, followed by drying afforded 0.56 g(quant) of the crude1-tert-butyl-3-[2′-hydroxy-5′-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]-urea.

1-tert-Butyl-3-[2′-hydroxy-5′-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]-urea(0.56 g, 1.5 mmol) was dissolved in a mixture of chloroform (0.2 mL, 3mmol) and sodium hydroxide (10% aqueous, 5 mL, 12 mmol) and the mixturewas refluxed for 5 days. The mixture was worked up with 1N hydrochloricacid and ethyl acetate. Some solids precipitated out of solution andwere filtered and dried. The organic layer from the extraction was driedand combined with the solids above gives1-tert-butyl-3-[3′-formyl-2′-hydroxy-5′-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]-ureaas a 3:1 mixture of starting material to product.

Reference 21 Synthesis ofN-(3-Phenylpropionyl)-5-formyl-6,2′-dimethoxy-biphenyl-sulfonamide

5-Formyl-6,2′-dimethoxy-biphenyl-3-sulfonamide (0.32 g, 1 mmol),prepared as in Reference 19, was dissolved along with triethylamine(0.125 g, 1.25 mmol) and 4-dimethylaminopyridine (0.012 g, 0.1 mmol) inmethylene chloride (30 mL) and then 3-phenylpropionyl chloride (0.2 g,1.15 mmol) was added dropwise to the solution. The mixture was stirredfor 12 hours and concentrated by rotoevaporation in vacuum. The residuewas partitioned between ethyl acetate and 5% aqueous citric acid and theorganic layer was separated washed with water and brine, dried overmagnesium sulfate and then concentrataed in vacuum to giveN-(3-phenylpropionyl)-5-formyl-6,2′-dimethoxy-biphenyl-sulfonamide (0.4g).

Proceeding as in Reference 21, but substituting3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenylpropionylchloride, gaveN-(3-phenylpropionyl)-3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and acetyl chloride,gave N-acetyl-5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and acetyl chloride,gave N-acetyl-3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and benzoyl chloride,gave N-benzoyl-5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and 4-phenylbutyrylchloride, gave5-formyl-6-methoxy-3′-nitro-N-(4-phenylbutyryl)-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and 2-phenylacetylchloride, gave5-formyl-6-methoxy-3′-nitro-N-(2-phenylacetyl)-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 4-phenylbutyrylchloride, gave3′-amino-5-formyl-6-methoxy-N-(4-phenylbutyryl)-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and3-(3,4-dichlorophenyl)-propanoyl chloride, gaveN-[3-(3,4-dichlorophenyl)-propanoyl]-5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and benzoyl chloride,gave N-benzoyl-3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting5-formyl-6-methoxy-3′-ureido-biphenyl-3-sulfonamide and 2-phenylacetylchloride, gave5-formyl-6-methoxy-N-(2-phenylacetyl)-3′-ureido-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting5-formyl-6,2′-dimethoxy-biphenyl-3-sulfonamide and 3-phenylpropionylchloride, gave5-formyl-6,2′-dimethoxy-N-(3-phenylpropionyl)-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting3′-chloro-5-formyl-6-methoxy-biphenyl-3-sulfonamide and3-phenylpropanoyl chloride, gave3′-chloro-5-formyl-6-methoxy-N-(3-phenylpropanoyl)-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenyl-propanoylchloride, gave5-formyl-6-methoxy-N-3-phenyl-propanoyl)-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and3-pyridin-3-ylpropanoyl chloride, gave5-formyl-6-methoxy-3′-nitro-N-(3-pyridin-3-ylpropanoyl)-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and3-pyridin-3-ylpropanoyl chloride, gave3′-amino-5-formyl-6-methoxy-N-(3-pyridin-3-ylpropanoyl)-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting5-formyl-6-methoxy-3′-ureido-biphenyl-3-sulfonamide and3-pyridin-3-ylpropanoyl chloride, gave5-formyl-6-methoxy-N-(3-pyridin-3-ylpropanoyl)-3′-ureido-biphenyl-3-sulfonamide.

Proceeding as in Reference 21, but substituting3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and3-piperidin-3-ylpropanoyl chloride, gave3′-amino-5-formyl-6-methoxy-N-(3-piperidin-3-ylpropanoyl)-biphenyl-3-sulfonamide.

Reference 22 Synthesis ofN-(3-phenylpropionyl)-5-formyl-6,2′-dihydroxy-biphenyl-3-sulfonamide

N-(3-Phenylpropionyl)-5-formyl-6,2′-dimethoxy-biphenyl-sulfonamide (0.4g, 0.88 mmol) was dissolved in methylene chloride (5 mL) and thesolution was stirred while a boron tribromide (2 mL, 1 M inmethylenechloride, 2 mmol) was added. The mixture was stirred for 36hours and then concentrated in vacuum. The residue was dissolved inethyl acetate and the solution was shaken with 5% aqueous sodiumbicarbonate (10 mL). The mixture was acidified to pH 3 with 5% aqueouscitric acid. The organic layer was separated, washed with water andbrine, dried over sodium sulfate and concentrated in vacuum to a minimalvolume. The residue was passed through short silica column, usinghexanes/ethyl acetate (1:1) to giveN-(3-phenylpropionyl)-5-formyl-6,2′-dihydroxy-biphenyl-3-sulfonamide(0.21 g, 53%). MS: found (M−H) 424.1, (M+H) 426.2, calc 425.09.

Proceeding as in Reference 22, but substituting3-bromo-4-methoxyphenylacetic acid (14.0 g, 0.057 mol) and borontribromide (63 mL, 1M in dichloromethane, 0.063 mol), gave3-bromo-4-hydroxyphenylacetic acid (12 g).

Reference 23[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]aceticacid

Methyl[5′-tert-butylsulfamoyl-5-formyl-2′-methoxy-6-2-methoxyethoxymethoxy)biphenyl-3-yl]acetate(0.496 g, 1.1 mmol), prepared as in Reference 8, was dissolved inmethanol (20 mL) and the solution was charged with3,4-diaminobenzamidine-HCl (1.25 mmol, 0.23 g) and 1,4-benzoquinone(1.25 mmol, 0.135 g). The mixture was refluxed for 2 hours and thenconcentrated by evaporation. This residue was taken up intrifluoroacetic acid (10 mL) and the mixture was stirred for 1 hour.Evaporation and further pumping down yielded a purple amorphous residue.Pyridine hydrochloride (5.0 g) was added and the reaction mixture washeated at 180° C. for 30 minutes. The mixture was cooled and a resultingsolid was dissolved in 20 mL of preparative hplc sample solvent (20%acetonitrile/20 mmol HCl). The product was purified by preparative hplc(C-18, 2,2,25 acetonitrile). The fractions containing the pure productwere collected and lyophilized to give[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-yl]aceticacid (0.31 g, 59%). LCMS: Calcd 481.49; Obsd (MH+)=482.0, (MH−)=480.2.NMR (DMSO-d₆) d 3.621 (s, 2H), 7.07 (d, J=8 Hz, 1H), 7.15 (br s, 2H),7.27 (d, J=2 Hz, 1H), 7.63 (d, J=2 Hz, 1H), 7.65 (m, 2H), 7.73 (d or d,J=2, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.08 (d, J=2 Hz, 1H), 8.17 (s,1H), 9.10, 9.39 (2s, 4H).

Proceeding as in Reference 23, but substituting3′-tert-butylsulfamoyl-5-formyl-6-(2-methoxyethoxymethoxy)-biphenyl-3-carboxylicacid methyl ester (1.64 g, 3.42 mmol, 1.0 eq.) and3,4-diamino-benzamidine hydrochloride (638 mg, 3.42 mmol, 1.0 eq.), gave5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-3′-sulfamoyl-biphenyl-3-carboxylicacid hydrochloride (650 mg) as a brown solid.

Proceeding as in Reference 23, but substituting6-benzyloxy-5′-fluoro-5-formyl-2′-methoxybiphenyl-3-carboxylic acidmethyl ester (1.3 g, 3.30 mmol) and 3,4-diaminobenzamidine hydrochloride(0.739 g, 3.96 mmol), gave5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-arboxylicacid (0.780 g).

Proceeding as in Reference 23, but substituting methyl5′-fluoro-5-formyl-6-hydroxy-2′-methoxymethoxy-biphenyl-3-yl)-acetate(400 mg, 1.1 mmol) and 3,4-diaminobenzamidine hydrochloride (235 mg, 1.2mmol), gave3-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-2-yl-aceticacid (201 mg, 40%).

Example 1 Synthesis of2-(2,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidinehydrochloride

1-tert-Butyl-3-[3′-formyl-6,2′-bis-(2-methoxyethoxymethoxy)-biphenyl-3-ylmethyl]-urea(0.6 g, 1.15 mmol), prepared as in Reference 19, diaminobenzamidinehydrochloride (0.3 g, 1.6 mmol) and 1,4-benzoquinone (0.124 g, 1.15mmol) were combined in methanol (15 mL) and the mixture was heated at60° C. and stirred for 2 hours. The mixture was cooled to roomtemperature and the solvent was removed by evaporation to yield2-[5′-3-tert-butylureidomethyl)-2,2′-bis-(2-methoxyethoxymethoxy)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine.

2-[5′-(3-tert-Butylureidomethyl)-(2,2′-bis-(2-methoxyethoxymethoxy)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidinewas dissolved in 4 M hydrogen chloride in dioxane (4 mL) and thesolution was stirred at room temperature for 1 hour. Solvent was removedby evaporation and the residue was dissolved in neat trifluoroaceticacid (5 mL). The solution was stirred at room temperature for 8 hoursand then concentrated by evaporation. Product was purified from theresidue by reverse preparative HPLC (acetonitrile/HCl/water) to give2-(2,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidinehydrochloride (33 mg). MS LCMS Q⁺417.439 (M+1) (calc.), Q⁻415.439 (M−1)(calc.), (obs.); Q⁺417.3 (M+1), Q⁻415.3 (M−1). ¹H-NMR (d₆-DMSO) δ ppm:4.03 (2 H, s), 6.78 (1 H, d, J=8 Hz), 6.99 (3 H, m), 7.25 (1 H, dd,J=7.6, 2 Hz), 7.65 (1 H, dd, J=8.8, 1.6 Hz), 7.76 (1 H, d, J=8.4 Hz),8.06 (1 H, dd, J=7.6, 0.8 Hz), 8.09 (1 H. br s), 8.91 (2 H, br s) and9.27 (2 H, br s).

Proceeding as in Example 1, but substituting1-tert-butyl-3-[5′-fluoro-3′-formyl-6,2′-bis-(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]-urea,gave2-(5-fluoro-2,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidinehydrochloride (Compound 1). MS LCMS 433.423 (M−1) (calc.), 435.423 (M+1)(calc.), (obs.); Q⁺435.3 (M+1), Q⁻433.3 (M−1). ¹H-NMR (d₆-DMSO) δ ppm:4.17 (2 H, s), 6.38 (1 H, br s), 6.87 (1 H, d, J=8.4 Hz), 7.07 (1 H, dd,J=8.4, 2.4 Hz), 7.12 (1 H, d, J=2 Hz), 7.2 (1 H, dd, J=9.2, 3.2 Hz),7.73 (1 H, br d, J=8 Hz), 7.86 (1 H, d, J=8 Hz), 8.01 (1 H, dd, J=9.2,2.8 Hz), 8.18 (1 H, br s), 8.96 (2 H, br s) and 9.35 (2 H, br s)

Proceeding as in Example 1, but substituting[3-formyl-4-2-methoxy-ethoxymethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrileand 1-[3-bromo-4-(2-ethoxyethoxymethoxy)-benzyl]-3-tert-butylurea, gave2-(5-cyanomethyl-2,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidinehydrochloride (Compound 21). MS LCMS Q⁺456.476 (M+1) (calc.), Q⁻454.476(M−1) (calc.), (obs.); Q⁺456.3 (M+1), Q⁻454.3 (M−1). ¹H-NMR (d₆-DMSO) δppm: 4.14 (2 H, s), 4.17 (2 H, s), 6.92 (1 H, d, J=9.2 Hz), 7.12 (2 H,m), 7.36 (1 H, d, J=2.4 Hz), 7.77 (1 H, d, J=8.4 Hz), 7.90 (1 H, d,J=8.8 Hz), 8.14 (1 H, d, J=1.6 Hz), 8.23 (1 H, br s), 9.0 (2 H, br s)and 9.4 (2 H, br s).

Proceeding as in Example 1, but substitutingN-tert-butyl-3′-formyl-2′-(2-methoxyethoxymethoxy)-5′-methyl-biphenyl-3-sulfonamide,gave2-(5-methyl-2-hydroxy-3′-aminosulfonylbiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidinehydrochloride (Compound 52). MS LCMS Q⁺422.479 (M+1) (calc.), Q⁻420.479(M−1) (calc.), (obs.); Q⁺422.3 (M+1), Q⁻420.3 (M−1). ¹H-NMR (d₆-DMSO) δppm: 2.34 (3 H, s), 7.3 (1 H, d, J=1.6 Hz), 7.32 (2 H, br s), 7.56 (1 H,t, J=8 Hz), 7.64 (1 H, br m), 7.73 (1 H, t of d, J=8.8, 1.2 Hz), 7.77 (2H, m), 7.98 (1 H, br s), 8.03 (1 H, t, J=1.2 Hz), 8.88 (2 H, br s) and9.28 (2 H, br s).

Proceeding as in Example 1, but substituting1-tert-butyl-3-[3′-formyl-2′-hydroxy-5′-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]urea,gave2-[2-hydroxy-5-(H-tetrazol-5-yl)-3′-ureidomethylbiphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(0.01 g) as a brown solid (Compound 56). LCMS calcd. 468.48; obsvd.(M+H) 469.1, (M−H) 467.2.

Example 2 Synthesis of5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-N-dimethyl-3′-sulfamoyl-biphenyl-3-carboxamidehydrochloride

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-3′-sulfamoyl-biphenyl-3-carboxylicacid hydrochloride (29 mg, 60 μmol, 1.0 eq.), prepared as in Reference23, triethylamine (17 mg, 120 μmol, 2.0 eq.),benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate(29 mg, 66 μmol, 1.1 eq.) and S-pyrrolidine-2-carboxamide (6.9 mg, 60μmol, 1.0 eq.) in anhydrous dimethyformamide (4 mL) were stirred atambient temperature for 21 hours and then a further half-equivalent ofeach reagent was added to the reaction mixture. The mixture was stirredfor 28 hours and then concentrated. A dimethyl amide by-product waspurified from the residue by reverse-phase preparative HPLC (5→30%acetonitrile/20 mM aqueous hydrochloric acid). Fractions containingproduct were concentrated by lyophilization to give5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-N-dimethyl-3′-sulfamoyl-biphenyl-3-carboxamidehydrochloride (1.8 mg, 6%) as a yellow-brown solid. ¹H NMR (400 MHz,d₆-DMSO/D₂O): δ 9.40-9.32 (brs, 2H), 8.95-8.86 (brs, 2H), 8.29 (s, 1H),8.17 (s, 1H), 8.10 (s, 1H), 7.88-7.84 (m, 2H), 7.82 (d, J=7.3 Hz, 1H),7.72 (d, J=8.4 Hz, 1H), 7.65 (t, J=7.3 Hz, 1H), 7.57 (s, 1H). 3.04 (brs,1H). m/z (LCMS-ESI): Q⁺4.79 (M+H); Q⁻477 (M−H).

Example 3 Synthesis of2-[5-(2S-aminocarbonylpyrrolidin-1-ylcazbonyl)-2,2′-dihydroxy-5′-fluorobiphenyl-3-yl]-1H-benzoimidazole-5-carboxamidinehydrochloride

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-carboxylicacid (0.030 g, 0.068 mmol), prepared as in Reference 23, was dissolvedin dimethylformamide (5 mL) and then S-pyrrolidine-2-carboxamide (0.0074g, 0.065 mmol) and benzotriazole-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (0.032 g, 0.072 mmol) were added to the solution.Triethylamine (0.018 mL, 0.130 mmol) was added and the mixture wasstirred for 24 hours and then was concentrated. Product was purifiedfrom the residue by reverse phase HPLC to give(S)-1-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-carbonyl]-pyrrolidine-2-carboxamidehydrochloride (9 mg) as a yellow powder. ¹H NMR (400 MHz, DMSO-d₆) δ9.34 (br-s, 1H), 8.93 (br-s, 1H), 8.42 (br-s, 1H), 8.17( br-s, 1H), 7.83(br-d, J=8.35, 1H), 7.72 (m, 1H), 7.42 (br-s, 1H), 7.05 (m, 2H), 6.93(m, 1H), 4.39 (t, J=7.12, 1H), 3.79 (m, 1H), 3.59 (m, 1H), 2.20 (m, 2H),1.85 (m, 2H). ESIMS m/z: M⁺503.1.

Example 4 Synthesis of1-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-carbonyl]-4R-hydroxy-pyrrolidine-2S-carboxylicacid hydrochloride

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-carboxylicacid (0.250 g, 0.565 mmol), prepared as in Reference 23, was dissolvedin N,N-dimethylformamide (7 mL) and then methyl(S)-trans-4-hydroxypyrrolidine-2-carboxylate (0.098 g, 0.538 mmol) and2,3,4-trimethyl-pyridine (0.228 g, 1.88 mmol) were added to thesolution. The mixture was cooled to 0° C. andO-(7-azabenzotrizol-1-yl)-1,2,3,3-tetramethyluroniumhexafluorophosphate(0.225 g, 0.592 mmol) was added. The mixture was stirred at 0° C. forone hour and then at room temperature for 20 hours. The mixture wasconcentrated and the residue taken up in 0.5 N hydrochloric acid (20mL). The mixture was heated to 80° C. and stirred for 6 hours. Themixture was concentrated and product purified from the residue byreverse phase HPLC to give1-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-carbonyl]-4R-hydroxy-pyrrolidine-2S-carboxylicacid hydrochloride (0.064 g) as a yellow powder. ¹H NMR (400 MHz,DMSO-d₆) δ 9.41 (br-s, 1H), 9.13 (br-s, 1H), 8.42 (br-s, 1H), 8.20(br-s, 1H), 7.85 (br-d, J=8.71, 1H), 7.75 (br-d, J=8.37, 1H), 7.58 (br-s,1H), 7.10 (m, 1H), 7.03 (m, 1H), 6.96 (m, 1H), 4.54 (t, J=8.39, 1H),4.31 (br-s, 1H), 3.97 (dd, J=11.64, 3.85, 1H), 3.50 (d, J=10.99, 1H),2.23 (m, 1H), 1.97 (m, 1H). ESIMS m/z: M⁺520.3

Example 5 Synthesis of5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-N-pyridin-4-ylmethyl-biphenyl-3-carboxamidehydrochloride

5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-carboxylicacid hydrochloride (100 mg, 0.226 mmol), prepared as in Reference 23,O-(7-azabenzotrizol-1-yl)-1,2,3,3-tetramethyluroniumhexafluorophosphatemonohydrate (37 mg, 0.242 mmol) and(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (46 mg, 0.237mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL). Themixture was stirred at room temperature for 1 hour and then4-aminomethylpyridine (27 mg, 0.248 mmol) was added to the mixture. Themixture was stirred at ambient temperature for 18 hours and thenconcentrated to a gum under high vacuum. The residue was dissolved in 5%acetonitrile/95% 20 mM hydrochloric acid (10 mL) and product purifiedvia preparative C₁₈ reverse phase HPLC (5% to 35% acetonitrile gradient,20 mM HCl aqueous to give5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-N-pyridin-4-ylmethyl-biphenyl-3-carboxamidehydrochloride (50 mg) as a tan powder. ¹H-NMR (d₆-DMSO) δ ppm: 9.45 (bs,2H), 9.20 (bs, 2H) 9.11 (d, J=1.6 Hz, 1H), 8.86 (d, J=6.4 Hz, 2H), 8.22(d, J=1.6 Hz, 1H), 8.04 (d, J=6.4 Hz, 2H), 8.00 (d, J=2.0 Hz, 1H), 7.85(d, J=8.0 Hz, 1H), 7.78 (dd, J=8.8, 1.6 Hz, 1H), 7.14-6.96 (m, 3H), 4.79(d, J=5.6 Hz, 2H): MS LCMS Q⁺497.174 (calc.), 497.2 (obs.), Q⁻495.158(calc.), 454.9 (obs).

Example 6 Synthesis of2-[3′-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-biphenyl-3-yl]-acetamide

Methyl [3′-formyl-6,2′-bis(2-methoxyethoxymethoxy)biphenyl-3-yl]acetate(1.2 g, 2.59 mmol), prepared as in Reference 19, was dissolved inmethanol (20 mL) and the solution was charged with3,4-diaminobenzamidine hydrochlroide (0.58 g, 3.11 mmol) and1,4-benzoquinone (0.28 g, 2.59 mmol). The mixture was refluxed for 3hours and then concentrated by evaporation. The residue was dissolved inmethanol (10 mL) and treated with 4 M hydrogen chloride in dioxane (10ImL). The solution was stirred for two hours and then concentrated byevaporation. The residue was dissolved in ammonia in methanol (20 mL, 7M). The solution was transferred to a sealed tube and heated at 60° fortwo days while stirring. The solution was cooled and concentrated.Product was purified from the residue by preparative hplc (2, 2, 30)acetonitrile. The desired fractions containing product were pooled andconcentrated by evaporation to give2-[3′-(5-carbamimidoyl-1H-benzoimnidazol-2-yl)-6,2′-dihydroxy-biphenyl-3-yl]-acetamide(420 mg). LCMS: Calcd 401.4; Obsd (MH+) 402.2, (MH−) 400.0. NMR(DMSO-d₆) d 3.26 (s, 2H), 6.80 (s, 1H), 6.83 (d, J=9 Hz, 1H), 7.07 (m,2H), 7.38 (m, 2H), 7.73 (d, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.16 (d,J=1 Hz, 1H), 8.18 (s, 1H), 9.03 (s, 2H), 9.39 (s, 2H).

Example 7 Synthesis of2-(2,2′-dihydroxy-5-(1H-tetrazol-5-yl)-3′-aminomethylbiphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine

3′-Formyl-6,2′-(2-methoxyethoxymethoxy)-5′-(2-methoxyethoxymethyl)-1H-tetrazol-5-ylbiphenyl-3-ylcarbonitrile(0.3 g, 0.5 mmol), 3,4-diaminobenzamidine hydrochloride (0.11 g, 0.6mmol) and 1,4-benzoquinone (0.05 g, 0.5 mmol) were combined in methanol(15 mL) and the mixture was refluxed for 4 hours. 4M hydrogen chloridein dioxane (3 mL) was added to the mixture and stirring was continued atroom temperature for 14 hours. The mixture was concentrated byevaporation. The residue was dried under high vacuum and then dissolvedin methanol (50 mL). The solution was subjected to hydrogenation(balloon) using 10% Pearlman's catalyst. Filtration and drying afforded2-(2,2′-dihydroxy-5-(1H-tetrazol-5-yl)-3′-aminomethylbiphenyl-3-yl]-1H-benzoimidazole-5-carboxamidineas the crude product (0.2 g, 88%). LCMS calcd. 441.17, obsrvd. (M+H)442.2, (M−H) 440.2.

Example 8 Synthesis of2-(2,2′-dihydroxy-5-(1H-tetrazol-5-yl)-3′-ureidomethyl-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine

2-(2,2′-Dihydroxy-5-(1H-tetrazol-5-yl)-3′-aminomethylbiphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(0.2 g 0.2 mmol), prepared as in Example 7, was dissolved in methanol(10 mL). The solution was treated with triethylamine (0.2 mL, 1.5 mmol)and then potassium cyanate (0.09 g, 1.1 mmol aqueous solution, 0.5 mL)was added in 3 portions over 1 hour. 1N hydrochloric acid (5 mL) wasadded and the mixture was stirred at 50° C. over 3 days. Drying affordedcrude product, which was subjected to purification by reverse phase HPLCto give2-(2,2′-dihydroxy-5-(1H-tetrazol-5-yl)-3′-ureidomethyl-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(0.008 g) as a brown solid. LCMS calcd. 484.47, obsrvd. (M+H) 485.1,(M−H) 483.1.

Example 9 Synthesis of2-(5-acetylsulfamoyl-2-hydroxy-3′-sulfamoyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine

N-acetyl-N′-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide(100 mg, 0.21 mmol), prepared as in Reference 19, was dissolved indichloromethane (10 mL). The solution was flushed with nitrogen for 5minutes and then boron tribromide (1.0 mL, 1M solution indichloromethane) was added. The mixture was stirred at room temperaturefor 1 hour and then concentrated under by evaporation under reducedpressure. The residue was partitioned between water and ethyl acetate.The organic layer was washed with brine and dried over anhydrousmagnesium sulfate. The residue was passed through a short silica plugwith pure ethyl acetate to give N-acetyl5-formyl-6-hydroxy-biphenyl-3,3′-disulfonamide (74 mg) as a colorlessoil.

N-acetyl 5-formyl-6-hydroxy-biphenyl-3,3′-disulfonamide (74 mg, 0.19mmol) was dissolved in methanol (10 mL)and stirred at room temperature.3,4-Diaminobenzamidine (39 mg, 0.21 mmol) and 1,4-benzoquinone (20 mg,0.2 mmol) were added to the solution and the mixture was refluxed for 1hour. The solvent was removed by rotary evaporation under reducedpressure and the residue was dissolved in water and acetonitrile andpurified by reverse phase HPLC (0.02N HCl/ACN) to give2-(5-acetylsulfarnoyl-2-hydroxy-3′-sulfamoyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine(14.1 mg) as a yellow amorphous powder. MS m/z: 527.4 (M−H⁺) and 529.3(M+H⁺). ¹H NMR (400 MHz, DMSO-d₆): δ 9.36 (bs, 2H), 8.94 (bs, 2H), 8.08(d, J=2.2 Hz, 1H), 8.22 (bs, 1H), 8.10 (t, J=1.5 Hz, 1H), 7.96 (d, J=2.2Hz, 1H) 7.89 (d, J=1.8 Hz, 1H), 7.87-7.85 (m, 2H), 7.76 )dd, J=10, 1.5Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.46 (s, 2H) and 1.96 (s, 3H).

Proceeding as in Example 9, but substitutingN-butyl-N′-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide(352 mg, 0.69 mmol) gave2-(5-butylsulfamoyl-2-hydroxy-3′-sulfamoyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine(Compound 15). MS m/z: 569.2 (M−H⁺) and 571.2 (M+H⁺). ¹H NMR (400 MHz,DMSO-d₆): δ 9.35 (bs, 2H), 8.91 (bs, 2H), 8.80 (s, 1H), 8.21 (t, J=1.5Hz, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.95 (t, J=1.5 Hz, 1H), 7.93 (t, J=1.5Hz, 1H), 7.87 (t, J=1.5 Hz, 1H), 7.85 (t, J=1.5 Hz, 1H), 7.75 (d, J=12.2Hz, 1H) 7.70 (t, J=8.0 Hz, 1H), 7.21 (s, 2H), 3.57 (t, J=8.0 Hz, 2H),1.71 (q, J=11.1, 11.1, 7.6 Hz, 2H), 1.43 (sext, J=22.2, 11.1, 7.6 Hz,2H), and 0.89 (t, J=7.3 Hz, 3H).

Proceeding as in Example 9, but substituting3′-formyl-4′-methoxyethoxymethoxy)-N-tert-butyl-biphenylsulfonamidewhich was dissolved in neat TFA (5 mL) and stirred overnight to give3′-formyl-4′-hydroxybiphenyl-3-sulfonic acid amide which was convertedto2-(2-hydroxy-3′-aminosulfonylbiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine(Compound 14). MS m/z: 406.2 (M−H⁺) and 408.3 (M+H⁺) ¹H NMR (400 MHz,DMSO-d₆): δ 9.35 (bs, 2H), 8.97 (bs, 2H), 8.23 (d, J=7.3 Hz, 1H), 8.11(t, J=1.5 Hz, 1H), 7.85 (t, J=1.5 Hz, 1H), 7.83 (t, J=1.5 Hz, 1H), 7.82(t, J=1.5 Hz, 1H), 7.80 (t, J=1.5 Hz, 1H), 7.31 (d, J=9.1 Hz, 1H) 7.64(t, J=8.1 Hz, 1H), 7.54 (dd, J=8.1, 1.5 Hz, 1H), 7.39 (s, 2H) and 7.19(t, J=7.7 Hz, 1H).

Example 10 Synthesis of2-[2,2′-dihydroxy-5-(3-phenylpropionylaminosulfonyl)biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine

N-(3-Phenylpropionyl)-5-formyl-6,2′-dihydroxy-biphenyl-3-sulfonamide(0.065 g, 0.15 mmol), prepared as in Reference 22,3,4-diaminobenzamidine hydrochloride (0.043 g 0.23 mmol) andbenzoquinone (0.018 g, 0.16 mmol) were combined in ethanol (15 mL) andthe mixture was heated under reflux for 1 hour. The solvent wasevaporated in vacuum and the product was purified from the residue byreverse phase HPLC (acetonitrile/0.02N HCl gradient) to give2-[2,2′-dihydroxy-5-(3-phenylpropionylaminosulfonyl)biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(0.033 g). ¹H NMR (DMSO-d₆): δ 2.50 ( t, J=7.7 Hz, 2H), 2.63 (t, J=7.7Hz, 2H), 6.82-7.22 (m, 9H), 7.72 (dd, J₁=9.2 Hz, J₂=1.7 Hz, 1H), 7.78(d, J=2.5 Hz, 1H), 7.84 (d, J=9.2 Hz, 1H), 8.18 ( s, 1H), 8.68 (d, J=2.5Hz, 1H), 8.99 (s, 2H), 9.34 (s, 2H), 12.06 (s, 1H). MS: found (M+H⁺)556.4, (M−H⁺) 554.4, calc 555.16.

Proceeding as in Example 10, but substituting5-formyl-6-methoxy-3′-nitro-N-(4-phenylbutyryl)-biphenyl-3-sulfonamide,gave2-[2-hydroxy-3′-nitro-5-4-phenyl-butyrylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine,Compound 115. MS: found (M+H⁺) 600.0, (M−H⁺) 597.6, calc. 598.16.

Proceeding as in Example 10, but substituting5-formyl-6-hydroxy-3′-nitro-N-(3-pyridin-3-yl-propionyl)-biphenyl-3-sulfonamide,gave2-[2-hydroxy-3′-nitro-5-(3-pyridin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(Compound 116). MS: found (M+H⁺) 586.4, (M−H⁺) 584.3, calc. 585.14.

Proceeding as in Example 10, but substituting3′-amino-5-formyl-6-hydroxy-N-(3-pyridin-3-yl-propionyl)-biphenyl-3-sulfonamide,gave2-[3′-amino-2-hydroxy-5-(3-pyridin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(Compound 117). MS: found (M+H⁺) 556.2, (M−H⁺) 554.3, calc. 555.17.

Example 11 Synthesis of2-[3′-amino-2-hydroxy-5-(4-phenyl-butyrylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine

2-[2-Hydroxy-3′-nitro-5-(4-phenyl-butrrylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(0.063 g, 0.1 mmol), prepared as in Example 10 was dissolved in methanol(3 mL) and saturated aqueous ammonium chloride (1 mL) was added to thesolution. The mixture was heated with iron powder (1 g) for 5-10minutes, filtered through celite and concentrated under reducedpressure. Product was purified from the residue by reverse phase HPLC(acetonitrile gradient) to give2-[3′-amino-2-hydroxy-5-(4-phenyl-butyrylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(0.017 g). MS: found (M+H⁺) 569.3, (M−H⁺) 567.4, calc. 568.19.

Example 12 Synthesis of2-[2-hydroxy-5-(3-pyridin-3-yl-propionylsulfamoyl)-3′-ureido-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine

2-[3′-Amino-2-hydroxy-5-3-pyridin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(0.015 g, 0.023 mmol), prepared as in Example 10, was dissolved in amixture of methanol and water and then triethylamine was added to bringthe solution to pH 9. The mixture was heated with potassium cyanate(0.018 g, 0.23 mmol) for 12 hour at 40° C., concentrated by evaporationunder reduced pressure and the crude product was purified by reversedphase HPLC (acetonitrile gradient) to give2-[2-hydroxy-5-3-pyridin-3-yl-propionylsulfamoyl)-3′-ureido-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(0.01 g). MS: found (M+H⁺) 599.5, (M−H⁺) 597.7, calc. 598.17.

Example 13 Synthesis of2-[3′-amino-2-hydroxy-5-(3-piperidin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine

2-[2-Hydroxy-3′-nitro-5-(3-pyridin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(0.031 g, 0.05 mmol), prepared as in Example 10, was dissolved intrifluoroacetic acid (5 mL) and the solution was subjected tohydrogenation at 50 psi over PtO₂ catalyst for 12 hours. The mixture wasconcentrated in vacuum and product was purified from the residue byreverse phase HPLC (acetonitrile gradient) to give2-[3′-amino-2-hydroxy-5-(3-piperidin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(0.01 g). MS: found (M+H⁺) 562.4, (M−H⁺) 560.6, calc. 561.22.

Example 14 Synthesis of2-(2,2′-dihydroxy-5-sulfamoyl-5′-ureidomethyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine

5′-Cyano-5-formyl-6,2′-dimethoxybiphenyl-3-sulfonic acid amide (0.35 g,1 mmole), prepared as in Reference 19, was heated with pyridinehydrochloride (3.5 g) at 185° C. for 2 hours. The melt was dissolved in1N hydrochloric acid (15 mL) and the solution was extracted with ethylacetate. The ethyl acetate layer was washed with water and brine, driedover magnesium sulfate and concentrated. The residue was dissolved inmethanol (25 mL) along with 3,4-diaminobenzamidine hydrochloride (0.21g, 1.1 mmol) and benzoquinone (0.11 g, 1.0 mmol). The mixture was heatedfor 4 hours and concentrated. The residue was washed with ethyl etherand then dissolved in a 2:1 mixture of methanol and 1N hydrochloric acid(25 mL). The solution was subjected to hydrogenation at atmosphericpressure over Pearlman's catalyst (0.1 g) for 2 hours. The mixture wasand the mother liquor was concentrated by evaporation under reducedpressure. The residue was dissolved in 2:1 mixture of methanol and waterand triethylamine was added to bring the solution to pH 10.

The mixture was heated with potassium cyanate (0.32 g, 4 mmol) for 16hours at 40 to 50° C. and then concentrated by evaporation. Product waspurified from the residue by reversed phase HPLC (acetonitrile gradient)to give2-(2,2′-dihydroxy-5-sulfamoyl-5′-ureidomethyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine(0.035 g). ¹H NMR (DMSO-d₆) δ 4.11 (s, 2H), 6.39 (br.s, 1H), 6.88 (d,J=8.8 Hz, 1H), 7.09-7.11 (m, 2H), 7.32 (br.s, 2H), 7.74 (dd, J₁=8.4 Hz,J₂=1.5 Hz, 1H), 7.81 (d, J=2.2 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 8.18 (s, 1H), 8.61 (d, J=2.2 Hz, 1H), 8.99 (s, 2H), 9.36 (s, 2H), 12.06 (s,1H). MS: found (M+H⁺) 496.3, (M−H⁺) 494.2, calc 495.13.

Example 15 Synthesis of2-[5-(5-arbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-N-(2-hydroxy-ethyl)-acetamide

3-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-2-yl-aceticacid (0.04 g, 0.09 mmol), prepared as in Reference 9, was dissolved indimethylformamide (1 mL) and then diisopropylethylamine (0.03 mL, 0.18mmol), 2-aminoethanol (0.008 mL, 0.14 mmol) andbromotripyrrolidinophos-phonium hexafluorophosphate (0.05 g, 0.12 mmol)was added to the solution. The mixture was stirred for 1 hour and thenconcentrated under vacuum. Product was purified from the residue byreverse phase HPLC to give2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-N-(2-hydroxy-ethyl)-acetamide(0.025 g, 61%) as an off-white solid. LCMS calcd. 463.47, obsrvd. (M+H)464.2, (M−H) 462.4.

Proceeding as in Example 15, but substituting 2-amino-propane-1,3-diol(0.013 g, 0.14 mmol), gave2-[2,2′-dihydroxy-5′-fluoro-5-(N-(1-hydroxymethyl-2-hydroxyethylaminocarbonylmethyl)biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine(0.015 g, 34%) as an off-white solid. LCMS calcd. 493.49, obsrvd. (M+H)494.1, (M−H) 492.3.

Example 16 Synthesis ofN-[3′-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-biphenyl-3-ylmethyl]-2-hydroxy-acetamide

tert-Butyl[3′-formyl-6,2′-bis(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]carbamate(0.284 g, 0.55 mmol) was dissolved in methanol (15 mL) and the solutionwas treated with diamino-benzamidine hydrocloride (0.112 g, 6.0 mmol)and 1,4-benzoquinone (65 mg, 6.0 mmol). The mixture was refluxed for 3hours and then concentrated by evaporation. The residue was dissolved inmethanol (15 mL) and hydrogen chloride (15 mL, 4M in dioxane) was addedto the solution. The mixture was stirred for one hour and thenconcentrated. Product was purified from the crude by preparative HPLC(2,2,25) (acetonitrile) to give2-(5′-aminomethyl-2,2′-dihydroxybiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine(210 mg).

2-(5′-Aminomethyl-2,2′-dihydroxybiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine(25 mg, 0.056 mmol) was dissolved in dimethylformamide (5 mL) andtriethylamine (0.030 g, 0.30 mmol, 0.042 mL) and2,5-dioxo-pyrrolidin-1-y acetoxyacetate (0.0215 g, 0.10 mmol) were addedto the solution. The mixture was stirred for 30 minutes and thenconcentrated by evaporation. The residue was combined with methanol (5mL) and potassium carbonate (1.0 mL, 1 M) and the mixture was stirredfor 1 hour. The reaction mixture was acidified to pH˜3 and thenconcentrated by evaporation. The residue was prepared at (2,2,25)(acetonitrile) to giveN-[3′-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-biphenyl-3-ylmethyl]-2-hydroxy-acetamide(17 mg). LCMS: Calcd=431.5; Obsd, (MH+)=432.2, (MH−)=430.2. NMR(DMSO-d₆) d 3.80 (s, 2H), 4.22 (d, J=6 Hz, 2H), 6.84 (d, J=8 Hz, 1H),7.07 (m, 2H), 7.33 (d of d, J=1.5, 8 Hz, 1H), 7.72 (d of d, J=3, 8 Hz,1H), 7.83 (d, J=8 Hz, 1H), 8.12 (m, 2H), 8.16 (br s, 1H), 8.98, 9.35(2s, 4H).

Example 172-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide

[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-aceticacid (96 mg, 0.20 mmol), prepared as in Reference 9, was dissolved indry N,N-dimethylformamide (20 mL) and the solution was treated withO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (84 mg, 0.22 mmol) and 2,3,4-trimethyl-pyridine(0.106 mL, 0.80 mmol). The mixture was stirred for one hour and then4-2-aminoethyl)-morpholine (29 uL, 0.22 mmol) was added. The mixture wasstirred until the reaction was complete (½ to 1 hours) and thenneutralizated with 1N hydrochloric acid to pH˜3. The solvents wereevaporated at 30° C. to give an oily residue. The crude amide then wasprepared at 2:30 (acetonitrile/20 mmol HCl) and the solvents werelyophilized to give2-[5-(5-arbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-2-morpholin-4-yl-ethyl)-acetamide(63.0 mg, 53%). LCMS: (MH+)=594.3; (MH−)=592.2. NMR (DMSO-d6) d 2.78 (m,4H), 3.12 (m, 2H), 3.26 (t, J=3 Hz, 2H), 3.57 (m, 4H), 3.59 (s, 2H),7.17 (d, J=5 Hz, 1H), 7.23 (br s, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.70 (m,2H), 7.79 (d of d, J=1,5 Hz, 1H), 7.88 (d, J=5 Hz, 1H), 8.22 (d, J=1 Hz,1H), 8.24 (s, 1H), 8.59 (t, J=3 Hz, 1H), 9.18, 9.43 (2s, 4H).

Proceeding as in Example 17, but substituting lithium2-aminoethanesulfonate (54 mg), prepared as in Reference 4, in hotdimethyl sulfoxide (4 mL) and triethylamine (200 uL), gave2-{2-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-ethanesulfonicacid (55 mg, 45%) (Compound 234). LCMS: (MH+)=589.1. (MH−)=587.2, NMR(DMSOd6) d 2.71 (t, J=6 Hz, 2H), 3.43 (t, J=6 Hz, 2H), 3.46 (t, J=6 Hz,1H), 7.03 (d, J=5 Hz, 1H), 7.18 (br s, 1H), 7.24 (d, J=1 Hz, 1H), 7.63(d of d, J=1, 5 Hz, 1H), 7.68-7.75 (m, 2H), 7.85 (d, J=5 Hz, 1H), 8.19(s, 1H), 8.26 (d, J=1 Hz, 1H), 8.43 (t, J=5 Hz, 1H), 8.86, 9.37 (2s,4H).

Proceeding as in Example 17, but substituting tert-butyl6-amino-2-tert-butoxycarbonylamino-hexanoate (0.65 g), prepared as inReference 5, gave2-amino-6-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino{-hexanoicacid (68 mg, 53%) (Compound 112). LCMS: (MH+)=610.4. (MH−)=608.6, NMR(DMSO-d6) d 1.3-1.5 (m, 2H), 1.8 (m, 2H), 3.08 (q, J=6 Hz, 2H), 3.51 (s,2H), 3.89 (q, J=6 Hz, 1H), 7.05 (d, J=5 Hz, 1H), 7.18 (br s, 1H), 7.31(d, J=1 Hz, 1H), 7.65 (m, 2H), 7.77 (d of d, J=1, 5 Hz, 1H), 7.83 (d,J=5 Hz, 1H), 8.14 (d, J=1 Hz, 1H), 8.21 (s, 1H), 8.38 (d, J=5 Hz, 2H),9.15, 9.42 (2s, 4H).

Proceeding as in Example 17, but substituting 1-methylpiperazine (25 uL)and triethylamine (40 uL), gave2-{2,2′-dihydroxy-5-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-5′-sulfamoyl-biphenyl-3-yl}-1H-benzoimidazole-5-carboxamidine(55 mg, 48%), Compound 113. LCMS: (MH+)=564.2; (MH−)=562.1; NMR(DMSO-d6) d 2.79 (s, 3H), 2.9-3.2 (m, 2H), 3.43 (t, J=6 Hz, 2H), 3.55(t, J=14 Hz, 1H), 3.70 (m, 1H), 3.80 (s, 2H), 4.33 (d, J=14 Hz, 1H),4.47 (d, J=14 Hz, 1H), 7.12 (d, J=5 Hz, 1H), 7.20 (br s, 1H), 7.24 (d,J=1 Hz, 1H), 7.6-7.8 (m, 2H), 7.75 (d, J=5 Hz, 1H), 7.84 (d, J=5 Hz,1H), 8.13 (d, J=1 Hz, 1H), 8.21 (s, 1H), 9.02, 9.41 (2s, 4H).

Proceeding as in Example 17, but substituting(2-aminoethyl)-trimethylammonium chloride (73 mg, 0.41 mmol) in amixture of dimethyl sulfoxide (4 mL) and triethylamine (57 uL) heated to80° C. which mixture was added in a dropwise fashion to the reactionmixture, gave(2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-ethyl)-trimethyl-ammonium(53 mg, 43%), Compound 105. NMR (DMSO-d6) d 3.05 (s, 9H), 3.42 (q, J=6Hz, 2H), 3.55 (m, 6H), 7.12 (d, J=5 Hz, 1H), 7.20 (br s, 1H), 7.30 (d,J=1 Hz, 1H1), 7.67 (m, 2H), 7.78 (d of d, J=1, 5 Hz, 1H), 7.83 (d,J=5Hz, 1H), 8.20 (m, 2H), 8.61 (t, J=6 Hz, 1H), 9.11, 9.41 (2s, 4H).

Proceeding as in Example 17, but substituting5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carboxylicacid, prepared as in Reference 10, gave N-(2-morpholin-4-yl-ethyl)5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carboxamideas a yellow solid, Compound 110. RP-HPLC (1-90S) RT=2.26 min. ¹H NMR(400 MHz, d₆-DMSO, selected signals): δ 10.40* (1H, v br s), 10.27* (1H,v br s), 9.36* (2H, s), 8.96* (3H, m), 8.80* (1H, br t, J=5.7 Hz), 8.18(1H s), 7.94 (1H, d, J=2.0 Hz), 7.85 (1H, d, J=8.4 Hz), 7.74 (1H, dd,J=8.4, 1.6 Hz), 7.69 (1H, d, J=2.0 Hz), 7.68 (1H, dd, J=8.4, 1.6 Hz),7.18* (2H, s), 7.08 (1H, d, J=8.4 Hz), 3.99 (2H, br m), 3.79 (2H, br m),3.71 (2H, br m), 3.58 (2H, m), 3.15 (2H, m); m/z (LCMS-ESI): Q⁺580(M+H); Q⁻578 (M−H).

Proceeding as in Example 17, but substituting5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carboxylicacid (20 mg, 40 μmol), prepared as in Reference 10, and lithium2-aminoethanesulfonate, prepared as in Reference 4, gave2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-ethanesulfonicacid as a yellow solid, Compound 111. RP-HPLC (1-90S) RT=2.21 min; ¹HNMR (400 MHz, d₆-DMSO, selected signals): δ 9.36* (2H, s), 8.98* (2H,s), 8.74(1 H, J=1.6 Hz), 8.74 (1H, d, J=2.0 Hz), 8.49* (1H, br t, J=5.0Hz), 8.17 (1H, s), 7.85 (1H, d, J=8.4 Hz), 7.81 (1H d, J=2.0 Hz), 7.75(1H, dd, J=8.4 Hz, 0.8 Hz), 7.70 (1H, dd, J=2.4 Hz), 7.67 (1H, dd,J=8.4, 2.4 Hz); 7.16* (2H, br s), 7.07 (1H, d, J=8.4 Hz); m/z(LCMS-ESI): Q⁺575 (M+H); Q⁻573 (M−H).

Proceeding by analogous methods provided in the Examples set forthherein gave:

2S-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-succinamicacid hydrochloride, Compound 121, ¹H NMR: 9.30 (2 H, br s), 8.87 (2 H,br s), 8.23 (d, 1 H, J=7.6 Hz), 8.09 (1 H, br s), 7.92 (1 H, br s), 7.76(d, 1 H, J=7.2 Hz), 7.65 (1 H, d, J=8.4 Hz), 7.6-7.57 (2 H, m), 7.38 (1H, s), 7.20 (1 H, d, J=2.4 Hz), 7.08 (1 H, br s), 6.97 (1 H, d, J=9.2Hz), 6.865 (1 H, br s), 4.47 (1 H, dd, J=7.6 and 5.6 Hz), 3.62 (2 H brs), 2.48 (2 H, d of ABq, J=15.2 and 5.6 Hz);

2R-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-succinicacid, Compound 123, H¹ NMR (CD₃DO-d4) 9.33 (s, 2 H) 8.94 (s, 2 H) 8.46(d, 1 H, J=7.8 Hz) 7.99 (d, 1 H, J=1.6 Hz) 7.839 (d, 1 H, J=8.6 Hz) 7.73(dd, 1 H, J=1.2 Hz, 8.6 Hz) 7.66 (d, 1 H, J=2.3 Hz) 7.661 (dd, 1H, J=2.7Hz, 8.6 Hz) 7.285 (d, 1 H, J=2.3 Hz) 7.051 (d, 1 H, 8.2 Hz) 4.57 (q, 1H, J=7.0 Hz, 14.1 Hz) 3.542 (s, 2 H) 2.741 (m, 1 H);

1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-pyrrolidine-2R-carboxamide,Compound 124, ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (br-s, 1H), 9.30 (br-s,1H), 8.85 (br-s, 1H), 8.15 (br-s, 1H), 7.98 (d, J=1.75, 1H), 7.83 (br-d,J=9.3, 1H), 7.70 (br-d, J=9.17, 1H), 7.64 (m, 2H), 7.36 (br-s, 1H), 7.25(d, J=2.02, 1H), 7.15 (s, 1H), 7.03 (d, J=8.08, 1H), 6.94 (br-s, 1H),4.25 (dd, J=5.64, 3.16, 1H), 3.72 (s, 2H), 3.59 (m, 1H), 3.30 (obsc-m,1H), 2.03 (m, 2H), 1.85 (m, 2H). ESIMS m/z: M⁺578.5;

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetamide,Compound 126, H¹ NMR (CD₃DO-d4) 3.621 (s, 2H) 7.07 (d, J=8 Hz, 1H) 7.15(br s, 2H) 7.27 (d, J=2 Hz, 1H) 7.63 (d, J=2 Hz, 1H) 7.65 (m, 2H) 7.73(d of d, J=2, J=8, 1H) 7.83 (d, J=8 Hz, 1H) 8.08 (d, J=2 Hz, 1H) 8.17(s, 1H) 9.10 (s, 2H) 9.39 (s, 2H);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N,N-dimethyl-acetamide,Compound 127, H¹ NMR (CD₃DO-d4) 9.49(s,1H), 9.00(s,1H), 8.30(s,1H),8.03(d,1H, J=8.7 Hz), 7.95(m, 2H, J=10.4 Hz), 7.87(m,2H, J=10.4 Hz),7.51(d,1H, J=2 Hz), 7.12(d,1H, J=8.4 Hz), 3.93(s,2H), 3.23(s,3H),3.05(s,3H); MS: calc 508.55; found 509.2 (M+1), 507.3 (M−1);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-2-hydroxy-1-hydroxymethyl-ethyl)-acetamide,Compound 128, ¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 8.97 (s, 1H),8.17 (s, 1H), 8.03 (d, 1H), 7.86 (t, 1H), 7.73 (dd, 1H), 7.67 (t, 1H),7.64 (d, 1H), 7.30 (d, 1H), 7.16 (br-s, 1H), 7.06 (d, 1H), 3.72 (m, 4H),3.52 (s, 2H) ESIMS m/z: M⁺555.2, M⁻553.4;

2-[5-5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-dimethylamino-ethyl)-acetamide(Compound 131), LCMS Calcd: 551; Obsd (MH) 551, H′-NMR: DMSO-d_(6:) 2.7(d, 6H), 3.1 (q, 2H), 3.4 (q, 2H), 3.45 (s, 2H), 7.0 (d, 1H), 7.1 (s,1H), 7.25 (s, 1H), 7.6 (d, 2H), 7.7 (d, 1H), 7.8 (d, 1H), 8.1 (s, 1H),8.15 (s, 1H), 8.4 (t, 1H), 9.0 (s, 2H), 9.3 (s, 2H), 10.2 (s, 1H);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-hydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(3-dimethylamino-propyl)-acetamide,Compound 132, LCMS Calcd: 565; Obsd (MH+) 566, H′-NMR: DMSO_d6: 1.85 (m,2H), 2.5(s, 6H), 2.8 (m, 2H), 3.1 (m, 2H), 3.2 (m, 2H), 4.6 (s, 2H), 7.1(d, 1H), 7.2 (s, 1H), 7.3 (s, 1H), 7.7 (s, 1H), 7.75 (d, 1H), 7.85 (d,1H), 8.1 (s, 1H), 8.2 (s, 1H), 8.3 (t, 1H), 9.0 (s, 2H), 9.4 (s, 2H),10.4 (s, 1H);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-N-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-acetamide(Compound 134), LC-MS: Calcd. 639.25, Observed. 640.6 (M+1), 638.5(M−1);

2-[5-(5-arbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(3S,4S,5R,6S-tetrahydroxy-tetrahydro-pyran-2R-ylmethyl)-acetamide(Compound 135), RP-HPLC (1-90S) RT=2.17 min; ¹H NMR (400 MHz,d₆-DMSO+D₂O, selected signals, as a 40:60 mixture of α:β nanomers): δ8.14 (1H, br s), 7.94 (1H, br d, J=2.0 Hz), 7.84 (1H, d, J=8.4 Hz), 7.71(1H, m), 7.68-7.66 (2H, m), 7.28 (1H, d, J=2.0 Hz), 7.05 (1H, d, J=8.4Hz), 4.91 (0.4H, d, J=3.6 Hz, α-anomer), 4.30 (0.6H, d, J=8.0 Hz,β-anomer; m/z (LCMS-ESI): Q⁺643.4 (M+H, calc. 643.2); Q⁻641.5 (M−H,calc. 641.2);2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2,4R,5S-trihydroxy-6R-hydroxymethyl-tetrahydro-pyran-3-yl)-acetamide(Compound 136), LCMS: Calcd 642.65; Obsd (MH+)=643.4, (MH−)=641.3.

NMR (DMSO-d6) d 3.18 (m, 1H), 3.4-3.8 (m, 8H), 4.8-5.3 (br s, 7H), 7.11(d, J=8 Hz, 1H), 7.20 (br s, 1H), 7.32 (d, J=2 Hz, 1H), 7.65 (d, J=2 Hz,1H), 7.68 (m, 2H), 7.77 (d of d, J=2, J=8 Hz, 1H), 7.85 (d, J=8 Hz, 1H),8.12 (d of d, J=2, J=8 Hz, 1H), 8.22 (s, 1H), 9.11, 9.42 (2s, 4H);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-N-(2R,3R,4R,5S,6-pentahydroxy-hexyl)-acetamide(Compound 137), RP-HPLC (1-90S) RT=2.20 min; ¹H NMR (400 MHz,d₆-DMSO+D₂O, selected signals, as 60:40 mixture of amide rotamers): δ8.14 (1H, s), 7.88 (1H, m), 7.84 (1H, d, J=8.8 Hz), 7.70 (1H, dd, J=8.4,1.6 Hz), 7.69-7.66 (2H, m), 7.25 (0.4H, d, J=2.0 Hz, 1st rotamer), 7.20(0.6H, d, J=2.0 Hz, 2nd rotamer), 7.05 (1H, m), 3.68-3.40 (8H, m), 3.14(1.2H, s, 1st rotamer), 2.88 (1.8H, s, 2nd rotamer); m/z (LCMS-ESI):Q⁺659.6 (M+H, calc. 659.2); Q⁻657.6 (M−H, calc. 657.2);

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-acetamide(Compound 138), ¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 8.98 (s, 1H),8.17 (d, 1H), 8.03 (d, 1H), 7.86 (d, 1H), 7.73 (dd, 1H), 7.67 (dd, 1H),7.50 (s, 1H), 7.30 (d, 1H), 7.16 (br-s, 1H), 7.06 (d, 1H), 4.21 (t, 1H),3.98 (m, 6H), 3.83 (s, 2H), ESIMS m/z: M⁺585.4, M⁻583.4;

2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-acetamide(Compound 139), LCMS: Calcd 494.53; Obsd (MH+)=495.1, (MH−)=493.1, NMR(DMSO-d6) d 2.62 (s, 3H), 3.49 (s, 2H), 7.08 (d, J=8 Hz, 1H), 7.18 (brs, 2H), 7.30 (d, J=2 Hz, 1H), 7.67 (d, J=2 Hz, 1H), 7.69 (m, 1H), 7.78(d of d, J=2, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.04 (m, 1H), 8.10 (d,J=2 Hz, 1H), 8.21 (s, 1H), 9.08, 9.41 (2s, 4H);

2S-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-succinamide(Compound 140), 1H NMR (IMSO-d6): 10.23 (br s, 1H), 9.33 (s, 2H), 8.94(s, 2H), 8.32 (d, 1H, J=8.4 Hz), 8.16 (s, 1H), 8.00 (s, 1H), 8.83 (d,1H, J=8.4 Hz), 7.71 (d, 1H, J=8.8 Hz), 7.66 (m, 2H), 7.62 (d, 1H, J=2.4Hz), 7.44 (s, 1H), 7.27 (d, 2H, J=2.0 Hz), 7.15 (s, 2H), 7.04 (d, 1H,J=8.4 Hz), 6.94 (s, 1H), 4.53 (dd, 1H, J=7.6, 8.4 Hz), 3.53 (br s, underwater peak), 2.56 (dd, 1H, J=5.2, 15.6 Hz), 2.42 (dd, 1H, J=8.4, 15.6Hz). LC-MS: Calcd. 594.16, Observed. 595.3 (M+1), 593.1 (M−1);

2-[5-(5-arbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-acetamidehydrochloride (Compound 141), ¹H NMR: 9.40 (2 H, br s), 9.07 (2 H, brs), 8.20 (1 H, br s), 8.14-8.05 (2 H, m), 7.87 (1 H, d, J=8 Hz), 7.76 (1H, dd, J=8 and 2 Hz), 7.70-7.65 (3 H, m), 7.31 (1 H, d, J=2.4 Hz), 7.09(8.4 Hz), 3.58-3.38 (14 H, m), 3.14 (2 H, q, J=6.8 Hz), 1.67 (2 H,quintet, J=6.4 Hz), 1.10 (3 H, t, J=7.2 Hz).

3′-(5-carbamimidoyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-6,2′-dihydroxy-biphenyl-3-carboxamide (Compound 239), Mass: Observed m/z. 417 (M+1) Calculated m/z 416(M+); and

2-(2,2′-dihydroxy-5′-ureido-biphenyl-3-yl)-1H-pyrrolo[3,2-b]pyridine-5-carboxamidine,Mass: Observed m/z 402 (M+2) Calculated m.z 401 (M+).

Biological Examples Example 1 In Vitro Factor VIIa Inhibitor Assay

Mixtures of human Factor VIIa (typically supplied at 7 nM) and testcompound (present at varying concentrations) in assay medium(comprising: NaCl, 150 mM (pH 7.4); CaCl₂, 5 mM; Tween-20, 0.05% ; DadeInnovin tissue factor [Dade Behring, Newark, Del., USA]; EDTA, 1.5 mM;and dimethylsulfoxide, 10%) were incubated for 30 minutes at roomtemperature. Next, reactions were initiated with the addition ofsubstrate [500 μM of CH—₃SO₂-D-ha-But-Arg-pNA (from Centerchem, Norwalk,Conn., USA)]. Hydrolysis of the chromogenic substrate was followedspectrophotometrically at 405 nm for five minutes. Initial velocitymeasurements calculated from the progress curves by a kinetic analysisprogram (Batch Ki; BioKin, Ltd., Pullman, Wash.) were used to determineapparent inhibition constants (apparent K_(i)'s).

Compounds of the invention tested by the above-described assay exhibitedinhibition of Factor VIIa.

Example 2 In Vitro Factor Xa Inhibitor Assay

Mixtures of human Factor Xa (typically supplied at 3 nM) (fromHaematologic Technologies, Essex Junction, Vt., USA) and test compound(varying concentrations) in assay medium (comprising: Tris, 50 mM (pH7.4); NaCl, 150 mM; CaCl₂, 5 mM; Tween-20, 0.05%; EDTA, 1 mM; anddimethylsulfoxide, 10%) were incubated for 30 minutes at roomtemperature. Next, reactions were initiated with the addition ofsubstrate [500 μM of CH—₃CO₂-D-Cha-Gly-Arg-pNA (from Centerchem,Norwalk, Conn., USA]. Hydrolysis of the chromogenic substrate wasfollowed spectrophotometrically at (405 nm) for five minutes. Apparentinhibition constants (apparent K_(i)'s) were calculated from the enzymeprogress curves using standard mathematical models.

Compounds of the invention tested by the above-described assay exhibitedinhibition of Factor Xa.

Example 3 Pharmacokinetic Assay

Rats with pre-implanted jugular vein catheters, which were filled withheparin/saline/PVP lock prior to shipment, were bought from CharlesRiver. Three rats were selected for each study, weighed, and injectedwith test compound by tail vein injection. Any residual test compoundwas retained and stored at −70° C. for later analysis.

Blood samples (0.25 mL each) were collected from the indwellingcatheters at specified times over 120 h. The catheters were flushed withphysiological saline immediately after each collection and filled withheparinized saline after each 8, 24 and 48 h collection. In the eventthat a catheter failed, blood samples were collected via theretro-orbital sinus under isoflurane anesthesia at the appropriate time.

Blood samples were placed in 0.5 mL Microtainer® tubes (lithiumheparin), shaken gently and stored on wet ice. The samples werecentrifuged for 10 minutes at 2400 rpm in a refrigerated centrifuged.Plasma samples (0.1 mL) from each tube were transferred to 0.5 mL Unisonpolypropylene vials (Sun-500210) and stored below −70° C. for lateranalysis by LC/MS-MS.

Example 4 In vitro Clotting Assays . . . aPTT and PT

Coagulation assays, activated partial thromboplastin time (aPTT) andprothrombin time (PT) were carried out based on the procedure describedin Hougie, C. Hematology (Williams, W. J., Beutler, B., Erslev, A. J.,and Lichtman, M. A., Eds.), pp. 1766-1770 (1990), McGraw-Hill, N.Y.

Briefly, the assays were performed using normal human citrated plasmaand were performed at 37° C. on a coagulometer (Electra 800) inaccordance with the manufacturer's instructions (Medical LaboratoryAutomation—Pleasantville, N.Y.). The instrument was calibrated withplasma immediately prior to collecting clotting times for samples withinhibitors. The aPTT and PT doubling concentrations were calculated byfitting inhibitor dose response curves to a modified version of the Hillequation.

Pharmaceutical Composition Examples

The following are representative pharmaceutical formulations containinga compound of Formula I.

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets. Quantity per Ingredient tablet, mg compound of thisinvention 400 cornstarch 50 croscarmellose sodium 25 lactose 120magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule. Quantity per Ingredient capsule, mg compoundof this invention 200 lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation

The following ingredients are mixed to form a suspension for oraladministration. Ingredient Amount compound of this invention 1.0 gfumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propylparaben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 gVeegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 mL colorings 0.5 mgdistilled water q.s. to 100 mL

Injectable Formulation

The following ingredients are mixed to form an injectable formulation.Ingredient Amount compound of this invention 1.2 g sodium acetate buffersolution, 0.4 M 2.0 mL HCl (1 N) or NaOH (1 N) q.s. to suitable pH water(distilled, sterile) q.s. to 20 mL

All of the above ingredients, except water, are combined and heated to60-70° C. with stirring. A sufficient quantity of water at 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. to 100 g.

Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing the compoundof the invention with Witepsol® H-15 (triglycerides of saturatedvegetable fatty acid; Riches-Nelson, Inc., New York), and has thefollowing composition: compound of the invention 500 mg Witepsol ® H-15balance

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

1. A compound of Formula I:

wherein: X¹, X², X³, and X⁴ are independently —N— or —CR⁵— wherein R⁵ ishydrogen, alkyl, or halo with the proviso that not more than three ofX¹, X², X³ and X⁴ are —N—; R¹ is hydrogen, alkyl, halo, carboxy oraminocarbonyl; R² is hydrogen, alkyl, or halo; R³ is hydrogen, halo,alkyl, alkoxy, haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfonyl,cyanoalkyl, tetrazol-5-yl, tetrazol-5-ylalkyl, hydroxyalkylcarbonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, oxalyl, —NHSO₂R(where R is alkyl, aryl aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,cycloalkylalkyl, heterocycloallyl or heterocycloalkylalkyl), —SO₂NHCOR⁶(where R⁶ is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, or heterocycloalkylalkyl), —SO₃H, -(alkylene)-SO₃H,—CONR⁷R⁸, —CHCF₃NR⁷R⁸ or —COCONR⁷R⁸ (where R⁷ is hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, carboxyalkyl, sulfoalkyl or phosphonoalkyland R⁸ is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl,aminocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl,-(alkylene)-(OCH₂CH₂)_(n) R^(b) (where n is an integer from 1 to 6 andR^(b) is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino),aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl,hetereocycloalkylaminocarbonylalkyl or3-heterocycloalkyl-2-hydroxypropyl or R⁷ and R⁸ together with thenitrogen atom to which they are attached form heterocycloalkylamino),-(alkylene)-CONR⁹R¹⁰ or -(alkylene)-CHCF₃NR⁹R¹⁰ (where R⁹ is hydrogen,hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl,sulfoalkyl or phosphonoalkyl and R¹⁰ is hydrogen, hydroxy, alkyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl,phosphonoalkyl, aminocarboxyalkyl, aminocarbonylcarboxyalkyl,trimethylammonioalkyl, aminocarbonylalkyl, alkylene)-(OCH₂CH₂)_(n) R^(b)(where n is an integer from 1 to 6 and R^(b) is hydrogen, alkyl,hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl,heteroaryl, heteroaralkyl, hetereocycloalkylalkyl,hetereocycloalkylaminocarbonylalkyl or3-heterocycloalkyl-2-hydroxypropyl or R⁹ and R¹⁰ together with thenitrogen atom to which they are attached form heterocycloalkylamino),—CONH SO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclalkyl, or heterocycloalkylalkyl),-(alkylene)-CONHSO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl),aminoalkyloxy, carboxyalkyloxy, aminocarbonylalkyloxy, hydroxyalkyloxy,—(OCH₂CH₂)_(n)—R^(b) (where n is an integer from 1 to 6 and R^(b) ishydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino),—NHCO-alkylene)-R^(a) (where R^(a) is hydroxy, alkoxy, or —NR⁷R⁸ whereR⁷ and R⁸ are as defined above), —OPO₃H₂, or -(alkylene)-OPO₃H₂; R^(x)is hydrogen, alkyl, alkylthio, halo, hydroxy, hydroxyalkyl, alkoxy,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, or nitro; R^(y)is hydrogen, alkyl, or halo; R^(z) is hydrogen, alkyl, haloalkyl,cycloalkyl, alkylthio, halo, hydroxy, hydroxyalkyl, nitro, cyano,alkoxy, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy,carboxyalkyloxy, aminocarbonylalkyloxy, haloalkoxy, carboxy,carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl,alkylsulfonyl, alkylsulfonylalkyl, arylsulfonyl, heteroarylsulfonyl,carbamimidoyl, hydroxycarbamimidoyl, alkoxycarbamimidoyl,alkylsulfonylamino, alkylsulfonylaminoalkyl, alkoxysulfonylamino,alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl,hydroxyalkoxyalkylaminocarbonyl, heterocycloalkylcarbonyl,heterocycloalkylcarbonylalkyl, heterocycloalkyl, heterocycloalkylalkyl,oxoheterocycloalkyl, oxoheterocycloalkylalkyl, heteroaryl,heteroaralkyl, ureido, alkylureido, dialkylureido, ureidoalkyl,alkylureidoalkyl, dialkylureidoalkyl, thioureido, thioureidoalkyl,—COR¹² (where R¹² is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oraminoalkyl), -(alkylene)-COR¹² (where R¹² is alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, or aminoalkyl), —CONR¹⁴R¹⁵ (where R¹⁴ ishydrogen or alkyl and R¹⁵ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,aryl, aralkyl, heteroaryl or heteroaralkyl or R¹⁴ and R¹⁵ together withthe nitrogen atom to which they are attached from heterocycloamino),-(alkylene)-CONR¹⁶R¹⁷ (where R¹⁶ is hydrogen, alkyl or hydroxyalkyl andR¹⁷ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl,heteroaryl or heteroaralkyl or R¹⁴ and R¹⁵ together with the nitrogenatom to which they are attached from heterocycloamino), —NR¹⁸R¹⁹ (whereR¹⁸ is hydrogen or alkyl and R¹⁹ is hydrogen, alkyl, acyl, aryl,aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR²⁰R²¹ (where R²⁰is hydrogen, alkyl, or hydroxyalkyl and R²¹ is hydrogen, alkyl, acyl,alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl orheteroaralkyl), —SO₂NR²²R²³ (where R²² is hydrogen or alkyl and R²³ ishydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl or R²² andR²³ together with the nitrogen atom to which they are attached fromheterocycloamino), -(alkylene)-SO₂NR²R²⁵ (where R²⁴ is hydrogen or alkyland R²⁵ is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkylor R²⁴ and R²⁵ together with the nitrogen atom to which they areattached from heterocycloamino), —NR²⁶SO₂NR²⁷R²⁸ (where R²⁶ and R²⁷ areindependently hydrogen or alkyl, and R²⁸ is hydrogen, alkyl, aryl,aralkyl, heteroaryl or heteroaralkyl or R²⁷ and R²⁸ together with thenitrogen atom to which they are attached from heterocycloamino),-(alkylene)-NR²⁹SO₂NR³⁰R³¹ (where R²⁹ and R³⁰ are independently hydrogenor alkyl, and R³¹ is hydrogen, alkyl, aryl, aralkyl, heteroaryl orheteroaralkyl or R³⁰ and R³¹ together with the nitrogen atom to whichthey are attached from heterocycloamino), —CONH-(alkylene)-NR³²R³³ whereR³² is hydrogen or alkyl and R³³ is alkyl), or aralkyl; and R¹³ ishydrogen, hydroxy, (C₁₋₁₀)alkoxy, —C(O)R³⁵ where R³⁵ is alkyl, aryl,haloalkyl, or cyanoalkyl, or —C(O)OR³⁶ where R³⁶ is alkyl, hydroxyalkyl,alkoxyalkyl, alkoxycarbonylalkyl, acyl, aryl, or haloalkyl; andindividual isomers, mixture of isomers, or a pharmaceutically acceptablesalt thereof, provided that when R³ is hydrogen, halo, alkyl, alkoxy,haloalkyl, haloalkoxy, —NHSO₂R, tetrazol-5-yl, tetrazol-5-ylalkyl,—CONR⁷R⁸ (where R⁷ is hydrogen or alkyl, and R⁸ is hydrogen or alkyl),-(alkylene)-CONR⁹R¹⁰ (where R⁹ and R¹⁰ together with the nitrogen atomto which they are attached form pyrrolidinyl), aminoalkyloxy,carboxyalkyloxy, or aminocarbonylalkyloxy; and R^(z) is hydrogen, alkyl,haloalkyl, halo, nitro, alkoxy, haloalkyl, carboxy, alkoxycarbonyl,—NR¹⁸R¹⁹ (where R¹⁸ is hydrogen or alkyl and R¹⁹ is hydrogen, alkyl,aryl or aralkyl), pyrrolidinylcarbonyl, —SO₂NR²²R²³ (where R²² and R²³are alkyl), carbamimidoyl, alkylsulfonylamino, alkylthio, ureido,—NHC(S)NH₂ or heterocycloamino, then R^(x) is hydroxy or hydroxyalkyl.2. A compound of claim 1 wherein: R³ is hydrogen, halo, alkyl, alkoxy,haloalkyl, haloalkoxy, cyanoalkyl, tetrazol-5-yl, tetrazol-5-ylalkyl,hydroxyalkylcarbonyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, —NHSO₂R (where R is alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylor heterocycloalkylalkyl), —SO₂NHCOR⁶ (where R⁶ is alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl),—CONR⁷R⁸ or —COCONR⁷R⁸ (where R⁷ is hydrogen, alkyl, alkoxyalkyl,carboxyalkyl, hydroxyalkyl or phosphonoalkyl and R⁸ is hydrogen, alkyl,alkoxyalkyl, -(alkylene)-(OCH₂CH₂)_(n) R^(b) (where n is an integer from1 to 6 and R^(b) is hydrogen, alkyl, hydroxy, alkoxy, amino oralkylcarbonylamino), aminoalkyl, aminocarbonylalkyl,aminocarbonylcarboxyalkyl, aminocarboxyalkyl, carboxyalkyl,hydroxyalkyl, phosphonoalkyl, sulfoalkyl, trimethylammonioalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl or hetereocycloalkylalkyl or R⁷ andR⁸ together with the nitrogen atom to which they are attached formheterocycloalkylamino), -alkylene)-CONR⁹R¹⁰ (where R⁹ is hydrogen,alkyl, alkoxyalkyl, carboxyalkyl, hydroxyalkyl or phosphonoalkyl and R¹⁰is hydrogen, alkyl, alkoxyalkyl, -(alkylene)-(OCH₂CH₂)_(n) R^(b) (wheren is an integer from 1 to 6 and R^(b) is hydrogen, alkyl, hydroxy,alkoxy, amino or alkylcarbonylamino), aminoalkyl, aminocarbonylalkyl,aminocarbonylcarboxyalkyl, aminocarboxyalkyl, carboxyalkyl,hydroxyalkyl, phosphonoalkyl, sulfoalkyl, trimethylammonioalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkylalkyl or R⁹ andR¹⁰ together with the nitrogen atom to which they are attached formheterocycloalkylamino), —CONH SO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclalkyl, or heterocycloalkylalkyl),or -(alkylene)-CONHSO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl),wherein any rings comprising R³ are optionally substituted with one tosix groups independently selected from hydroxy, hydroxyalkyl,alkoxyalkyl, carboxy, alkoxycarbonyl, aminoalkyl, guanidinoalkyl, alkylor —CONR^(a)R^(b) where R^(a) and R^(b) are independently hydrogen oralkyl; and R^(z) is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio,halo, hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl,alkoxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy, carboxyalkyloxy,aminocarbonylalkyloxy, haloalkoxy, carboxy, carboxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl,alkylsulfonylalkyl, arylsulfonyl, heteroarylsulfonyl, carbamimidoyl,hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino,alkylsulfonylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl,heterocycloalkylalkylaminocarbonyl, hydroxyalkoxyalkylaminocarbonyl,heterocycloaLkylcarbonyl, heterocycloalkylcarbonylalkyl,heterocycloalkyl, heterocycloalkylalkyl, oxoheterocycloalkyl,oxoheterocycloalkylalkyl, heteroaryl, heteroaralkyl, ureido,alkylureido, dialkylureido, ureidoalkyl, alkylureidoalkyl,dialkylureidoalkyl, thioureido, thioureidoalkyl, —COR¹² (where R¹² isalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl),-(alkylene)-COR¹² (where R¹² is alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, or amninoalkyl), —CONR¹⁴R¹⁵ (where R¹⁴ is hydrogen or alkyland R¹⁵ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl,heteroaryl or heteroaralkyl or R¹⁴ and R¹⁵ together with the nitrogenatom to which they are attached from heterocycloamino),-(alkylene)-CONR¹⁶R¹⁷ (where R¹⁶ is hydrogen, alkyl or hydroxyalkyl andR¹⁷ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl aralkyl,heteroaryl or heteroaralkyl or R¹⁴ and R¹⁵ together with the nitrogenatom to which they are attached from heterocycloamino), —NR¹⁸R¹⁹ (whereR¹⁸ is hydrogen or alkyl and R¹⁹ is hydrogen, alkyl, acyl, aryl,aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR²⁰R²¹ (where R²⁰is hydrogen, alkyl, or hydroxyalkyl and R²¹ is hydrogen, alkyl, acyl,alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl orheteroaralkyl), —SO₂NR²²R²³ (where R²² is hydrogen or alkyl and R²³ ishydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl or R²² andR²³ together with the nitrogen atom to which they are attached fromheterocycloamino), -(alkylene)-SO₂NR²⁴R²⁵ (where R²⁴ is hydrogen oralkyl and R²⁵ is hydrogen, alkyl, aryl, aralkyl, heteroaryl orheteroaralkyl or R²⁴ and R²⁵ together with the nitrogen atom to whichthey are attached from heterocycloamino), —NR²⁶SO₂NR²⁷R²⁸ (where R²⁶ andR²⁷ are independently hydrogen or alkyl, and R²⁸ is hydrogen, alkyl,aryl, aralkyl, heteroaryl or heteroaralkyl or R²⁷ and R²⁸ together withthe nitrogen atom to which they are attached from heterocycloamino),-alkylene)-NR²⁹SO₂NR³⁰R³¹ (where R²⁹ and R³⁰ are independently hydrogenor alkyl, and R³¹ is hydrogen, alkyl, aryl, aralkyl, heteroaryl orheteroaralkyl or R³⁰ and R³¹ together with the nitrogen atom to whichthey are attached from heterocycloamino), —CONH-(alkylene)-NR³²R³³ whereR³² is hydrogen or alkyl and R³³ is alkyl), or aralkyl; and R¹³ ishydrogen, hydroxy, (C₁₋₁₀)alkoxy, —C(O)R³⁵ where R³⁵ is alkyl, aryl,haloalkyl, or cyanoalkyl, or —C(O)OR³⁶ where R³⁶ is alkyl, hydroxyalkyl,acyl, or haloalkyl; or a pharmaceutically acceptable salt thereof.
 3. Acompound of claim 2 in which R³ is —CONR⁷R⁸, —CH₂CONR⁹R¹⁰ or—C(CH₃)₂CONR⁹R¹⁰ wherein: R⁷ and R⁸ or R⁹ and R¹⁰ both are hydrogen,carboxymethyl, 2-hydroxyethyl or 2-phosphonoethyl or R⁷ or R⁹ ishydrogen or methyl and R⁸ or R¹⁰, respectively, is aminocarbonylmethyl,1,2-aminocarbonylethyl, 2-aminocarbonyl-1-carboxyethyl,5-amino-5-carboxypentyl, 2-carboxyethyl, carboxymethyl,2-carboxy-3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl, dimethylaminomethyl,3-dimethylaminopropyl, 2-hydroxy-1,1-bis-hydroxymethyl-ethyl,2-hydroxy-1-hydroxymethylethyl, 1,2-dicarboxyethyl, methyl,2-[2-(2-methylaminoethoxy)ethoxy]ethyl, 2-(4-methylpiperazin-1-yl)ethyl,2-morpholin-4-ylethyl, 2,3,4,5,6-pentahydroxy-hexyl,2-piperazin-1-ylethyl, 2-sulfoethyl,3,4,5,6-tetrahydroxy-etrahydro-pyran-2-ylmethyl,2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl,2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl-methyl,trimethylammonioethyl or 2-phosphonoethyl or R⁷ and R⁸ or R⁹ and R¹⁰together with the nitrogen atom to which they are attached form2-aminocarbonylpyrrolidin-1-yl, 2-carboxy4-hydroxypyrrolidin-1-yl or4-methylpiperazin-1-yl; R^(x) is hydroxy at the 2′-position; and R^(z)is aminosulfonyl or ureidomethyl at the 5 position; or apharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim
 1. 5. A methodof treating a disease in an animal mediated by Factor VIIa which methodcomprises administering to said animal a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 1and a pharmaceutically acceptable carrier.
 6. The method of claim 3wherein the disorder is a thromboembolic disorder.
 7. A method oftreating a a thromboembolic disorder, which method comprisesadministering to said animal a pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim 1 in combination with anotheranticoagulant agent(s) independently selected from a group consisting ofa thrombin inhibitor, a factor IXa, a factor Xa inhibitor, Aspirin®, andPlavis®.
 8. A method for inhibiting the coagulation of a biologicalsample comprising the administration of a compound of claim
 1. 9. Anintermediate of Formula II:

wherein: R¹ is hydrogen, alkyl, halo, carboxy or aminocarbonyl; R² ishydrogen, alkyl, or halo; R³ is hydrogen, halo, alkyl, alkoxy,haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfonyl, cyanoalkyl,tetrazol-5-yl, tetrazol-5-ylalkyl, hydroxyalkylcarbonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, oxalyl, —NHSO₂R (where R isalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl), —SO₂NHCOR⁶(where R⁶ is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, or heterocycloalkylalkyl), —SO₃H, -(alkylene)-SO₃H,—CONR⁷R⁸, —CHCF₃NR⁷R⁸ or —COCONR⁷R⁸ (where R⁷ is hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, carboxyalkyl, sulfoalkyl or phosphonoalkyland R⁸ is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl,aminocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl,-(alkylene)-(OCH₂CH₂)_(n) R^(b) (where n is an integer from 1 to 6 andR^(b) is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino),aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl,hetereocycloalkylaminocarbonylalkyl or3-heterocycloalkyl-2-hydroxypropyl or R⁷ and R⁸ together with thenitrogen atom to which they are attached form heterocycloalkylamino),{alkylene)-CONR⁹R¹⁰ or -(alkylene)-CHCF₃NR⁹R¹⁰ (where R⁹ is hydrogen,hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl,sulfoalkyl or phosphonoalkyl and R¹⁰ is hydrogen, hydroxy, alkyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl,phosphonoalkyl, aminocarboxyalkyl, aminocarbonylcarboxyalkyl,trimethylammonioalkyl, aminocarbonylalkyl, -alkylene)-(OCH₂CH₂)_(n)R^(b) (where n is an integer from 1 to 6 and R^(b) is hydrogen, alkyl,hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl,heteroaryl, heteroaralkyl, hetereocycloalkylalkyl,hetereocycloalkylaminocarbonylalkyl or3-heterocycloalkyl-2-hydroxypropyl or R⁹ and R¹⁰ together with thenitrogen atom to which they are attached form heterocycloalkylamino),—CONHSO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclalkyl, or heterocycloalkylalkyl),-(alkylene)-CONHSO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl),aminoalkyloxy, carboxyalkyloxy, aminocarbonylalkyloxy, hydroxyalkyloxy,—(OCH₂CH₂)_(n)—R^(b) (where n is an integer from 1 to 6 and R^(b) ishydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino),—NHCO-alkylene)-R^(a) (where R^(a) is hydroxy, alkoxy, or —NR⁷R⁸ whereR⁷ and R⁸ are as defined above), —OPO₃H₂, or -(alkylene)-OPO₃H₂; R^(x)is hydrogen, alkyl, alkylthio, halo, hydroxy, hydroxyalkyl, alkoxy,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, or nitro; R^(y)is hydrogen, alkyl, or halo; and R^(z) is hydrogen, alkyl, haloalkyl,cycloalkyl, alkylthio, halo, hydroxy, hydroxyalkyl, nitro, cyano,alkoxy, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy,carboxyalkyloxy, aminocarbonylalkyloxy, haloalkoxy, carboxy,carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl,alkylsulfonyl, alkylsulfonylalkyl, arylsulfonyl, heteroarylsulfonyl,carbamimidoyl, hydroxycarbamnimidoyl, alkoxycarbaminmidoyl,alkylsulfonylamino, alkylsulfonylaminoalkyl, alkoxysulfonylamino,alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl,hydroxyalkoxyalkylaminocarbonyl, heterocycloalkylcarbonyl,heterocycloalkylcarbonylalkyl, heterocycloalkyl, heterocycloalkylalkyl,oxoheterocycloalkyl, oxoheterocycloalkylalkyl, heteroaryl,heteroaralkyl, ureido, alkylureido, dialkylureido, ureidoalkyl,alkylureidoalkyl, dialkylureidoalkyl, thioureido, thioureidoalkyl,—COR¹² (where R¹² is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oraminoalkyl), -(alkylene)-COR¹² (where R¹² is alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, or aminoalkyl), —CONR¹⁴R¹⁵ (where R¹⁴ ishydrogen or alkyl and R¹⁵ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-CONR¹⁶R¹⁷(where R¹⁶ is hydrogen, alkyl or hydroxyalkyl and R¹⁷ is hydrogen,alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl), —NR¹⁸R¹⁹ (where R¹⁸ is hydrogen or alkyl and R¹⁹ ishydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, or heteroaralkyl),-(alkylene)-NR²⁰R²¹ (where R²⁰ is hydrogen, alkyl, or hydroxyalkyl andR²¹ is hydrogen, alkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl), —SO₂NR²²R²³ (where R²² ishydrogen or alkyl and R²³ is hydrogen, alkyl, aryl, aralkyl, heteroaryl,or heteroaralkyl, or R²² and R²³ together with the nitrogen atom towhich they are attached from heterocycloamino), -(alkylene)-SO₂NR²⁴R²⁵(where R²⁴ is hydrogen or alkyl and R²⁵ is hydrogen, alkyl, aryl,aralkyl, heteroaryl, or heteroaralkyl or R²⁴ and R²⁵ together with thenitrogen atom to which they are attached from heterocycloamino),—NR²⁶SO₂NR²⁷R²⁸ (where R²⁶ and R²⁷ are independently hydrogen or alkyl,and R²⁸ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkylor R²⁷ and R²⁸ together with the nitrogen atom to which they areattached from heterocycloamino), -(alkylene)-NR²⁹SO₂NR³⁰R³¹ (where R²⁹and R³⁰ are independently hydrogen or alkyl, and R³¹ is hydrogen, alkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl or R³⁰ and R³¹ together withthe nitrogen atom to which they are attached from heterocycloamino),—CONH-(alkylene)-NR³²R³³ where R³² is hydrogen or alkyl and R³³ isalkyl), or aralkyl.
 10. A process of preparing a compound of claim 1where X¹ is —N— comprising reacting a compound of Formula II:

with a compound of Formula III:

wherein: R³ is hydrogen, halo, alkyl, alkoxy, haloalkyl, haloalkoxy,haloalkylthio, haloalkylsulfonyl, cyanoalkyl, tetrazol-5-yl,tetrazol-5-ylalkyl, hydroxyalkylcarbonyl, aminosulfonyl,alkylarninosulfonyl, dialkylaminosulfonyl, oxalyl, —NHSO₂R (where R isalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl), —SO₂NHCOR⁶(where R⁶ is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, or heterocycloalkylalkyl), —SO₃H, -(alkylene)-SO₃H,—CONR⁷R⁸. —CHCF₃NR⁷R⁸ or —COCONR⁷R⁸ (where R⁷ is hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, carboxyalkyl, sulfoalkyl or phosphonoalkyland R⁸ is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl,aminocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl,-(alkylene)-(OCH₂CH₂)_(n) R^(b) (where n is an integer from 1 to 6 andR^(b) is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino),aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl,hetereocycloalkylaminocarbonylalkyl or3-heterocycloalkyl-2-hydroxypropyl or R⁷ and R⁸ together with thenitrogen atom to which they are attached form heterocycloalkylamino),-(alkylene)-CONR⁹R¹⁰ or -alkylene)-CHCF₃NR⁹R¹⁰ (where R⁹ is hydrogen,hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl,sulfoalkyl or phosphonoalkyl and R¹⁰ is hydrogen, hydroxy, alkyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl,phosphonoalkyl, aminocarboxyalkyl, aminocarbonylcarboxyalkyl,trimethylammonioalkyl, aminocarbonylalkyl, -(alkylene)-(OCH₂CH₂)_(n)R^(b) (where n is an integer from 1 to 6 and R^(b) is hydrogen, alkyl,hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl,heteroaryl, heteroaralkyl, hetereocycloalkylalkyl,hetereocycloalkylaminocarbonylalkyl or3-heterocycloalkyl-2-hydroxypropyl or R⁹ and R¹⁰ together with thenitrogen atom to which they are attached form heterocycloalkylamino),—CONHSO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclalkyl, or heterocycloalkylalkyl),-(alkylene)-CONHSO₂R¹¹ (where R¹¹ is alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl),aminoalkyloxy, carboxyalkyloxy, aminocarbonylalkyloxy, hydroxyalkyloxy,—(OCH₂CH₂)_(n)—R^(b) (where n is an integer from 1 to 6 and R^(b) ishydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino),—NHCO-alkylene)-R^(a) (where R^(a) is hydroxy, alkoxy, or —NR⁷R⁸ whereR⁷ and R⁸ are as defined above), —OPO₃H₂, or -(alkylene)-OPO₃H₂; andR^(z) is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio, halo,hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl,alkoxyalkyloxy, hydroxyalkoxyloxy, aminoalkyloxy, carboxyalkyloxy,aminocarbonylalkyloxy, haloalkoxy, carboxy, carboxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl,alkylsulfonylalkyl, arylsulfonyl, heteroarylsulfonyl, carbamimidoyl,hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino,aminosulfonyl, alkylsulfonylaminoalkyl, alkoxysulfonylamino,alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl,hydroxyalkoxyalkylaminocarbonyl, heterocycloalkylcarbonyl,heterocycloalkylcarbonylalkyl, heterocycloalkyl, heterocycloalkylalkyl,oxoheterocycloalkyl, oxoheterocycloalkylalkyl, heteroaryl,heteroaralkyl, ureido, alkylureido, dialkylureido, ureidoalkyl,alkylureidoalkyl, dialkylureidoalkyl, thioureido, thioureidoalkyl,—COR¹² (where R¹² is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oraminoalkyl), -(alkylene)-COR¹² (where R¹² is alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, or aminoalkyl), —CNNR¹⁴R¹⁵ (where R¹⁴ ishydrogen or alkyl and R¹⁵ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl), -alkylene)-CONR¹⁶R¹⁷(where R¹⁶ is hydrogen, alkyl or hydroxyalkyl and R¹⁷ is hydrogen,alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl), —NR¹⁸R¹⁹ (where R¹⁸ is hydrogen or alkyl and R¹⁹ ishydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, or heteroaralkyl),-(alkylene)-NR²⁰R²¹ (where R²⁰ is hydrogen, alkyl, or hydroxyalkyl andR²¹ is hydrogen, alkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl), —SO₂NR²²R²³ (where R²² ishydrogen or alkyl and R²³ is hydrogen, alkyl, aryl, aralkyl, heteroaryl,or heteroaralkyl, or R²² and R²³ together with the nitrogen atom towhich they are attached from heterocycloamino), -alkylene)-SO₂NR²⁴R²⁵(where R²⁴ is hydrogen or alkyl and R²⁵ is hydrogen, alkyl, aryl,aralkyl, heteroaryl, or heteroaralkyl or R²⁴ and R²⁵ together with thenitrogen atom to which they are attached from heterocycloamino),—NR²⁶SO₂NR²⁷R²⁸ (where R²⁶ and R²⁷ are independently hydrogen or alkyl,and R²⁸ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkylor R²⁷ and R²⁸ together with the nitrogen atom to which they areattached from heterocycloamino), -(alkylene)-NR²⁹SO₂NR³⁰R³¹ (where R²⁹and R³⁰ are independently hydrogen or alkyl, and R³¹ is hydrogen, alkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl or R³⁰ and R³¹ together withthe nitrogen atom to which they are attached from heterocycloamino),—CONH-(alkylene)-NR³²R³³ where R³² is hydrogen or alkyl and R³³ isalkyl), or aralkyl; and R¹³ is hydrogen; (i) optionally modifying any ofthe R¹, R², R³, R^(x), R^(y), R^(z), and R¹³ groups; (ii) optionallyisolating individual isomers; (iii) optionally preparing an acidaddition salt; and (iv) optionally preparing a free base; (v) optionallypreparing an acid addition salt; and (vi) optionally preparing a freebase.